Dihydropyrrolo[1,2-a]indole and tetrahydropyrido[1,2-a]-indole derivatives as prostaglandin d2 receptor antagonists

ABSTRACT

Dihydropyrroloindoles and tetrahydropyridoindoles are prostaglandin receptor antagonists useful for the treatment of prostaglandin-mediated diseases such as allergic rhinitis, nasal congestion and asthma.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to compounds and methods fortreating prostaglandin mediated diseases, and certain pharmaceuticalcompositions thereof. More particularly, the compounds of the inventionare structurally different from steroids, antihistamines or adrenergicagonists, and are antagonists of the nasal and pulmonary congestioneffects of D-type prostaglandins.

[0002] Two review articles describe the characterization and therapeuticrelevance of the prostanoid receptors as well as the most commonly usedselective agonists and antagonists: Eicosanoids: From Biotechnology toTherapeutic Applications, Folco, Samuelsson, Maclouf, and Velo eds,Plenum Press, New York, 1996, chap. 14, 137-154 and Journal of LipidMediators and Cell Signalling, 1996, 14, 83-87. An article from T. Tsuriet al. published in 1997 in Journal of Medicinal Chemistry, vol 40,pp.3504-3507, states that “PGD2 is considered to be an importantmediator invarious allergic diseases such allergic rhinitis, atopicasthma, allergic conjunctivitis and atopic dermatitis.” More recently,an article by Matsuoka et al. in Science (2000), 287:2013-7, describesPGD2 as being a key mediator in allergic asthma. In addition, patentssuch as U.S. Pat. No. 4,808,608 refer to prostaglandin antagonists asuseful in the treatment of allergic diseases, and explicitly allergicasthma. PGD2 antagonists are described in, for example, European PatentApplication 837,052 and PCT Application WO98/25919, as well asWO99/62555.

[0003] In Arch. Pharm. (1972), 305(2): 96-103 there is disclosed thecompound

SUMMARY OF THE INVENTION

[0004] The present invention provides novel compounds which areprostaglandin receptor antagonists; more particularly, they areprostaglandin D2 receptor (DP receptor) antagonists. Compounds of thepresent invention are useful for the treatment of variousprostaglandin-mediated diseases and disorders; accordingly the presentinvention provides a method for the treatment of prostaglandin-mediateddiseases using the novel compounds described herein, as well aspharmaceutical compositions containing them.

DETAILED DESCRIPTION OF THE INVENTION

[0005] The present invention relates to compounds of formula I:

[0006] and pharmaceutically acceptable salts and hydrates thereof,wherein:

[0007] R¹, R² and R³ are each independently selected from hydrogen andR^(g);

[0008] R⁴ is selected from H, CN, C₁₋₆alkyl optionally substituted withone to six halogen,

[0009] OR^(a) and S(O)_(n)C₁₋₆alkyl;

[0010] R⁵ is selected from H and C₁₋₆alkyl optionally substituted withone to six halogen; or

[0011] R⁴ and R⁵ together represent an oxo; or

[0012] R⁴ and R⁵ taken together form a 3- or 4-membered ring containing0 or 1 heteroatom selected from NR^(f), S, and O optionally substitutedwith one or two groups selected from F, CF₃ and CH₃;

[0013] R⁶ is selected from H and C₁₋₆alkyl optionally substituted withone to six groups independently selected from OR^(a) and halogen,

[0014] Ar is aryl or heteroaryl each optionally substituted with one tofour groups independently selected from R^(g);

[0015] A is C₁₋₃alkyl optionally substituted with one to four halogenatoms, O(CH₂)₁₋₂, S(CH₂)₁₋₂;

[0016] Q is selected from:

[0017] (1) COOH,

[0018] (2) CONR^(a)R^(b),

[0019] (3) C(O)NHSO₂R^(c),

[0020] (4) SO₂NHR^(a),

[0021] (5) SO₃H,

[0022] (6) PO₃H₂, and

[0023] (7) tetrazolyl,

[0024] Y¹ is —(CR^(d)R^(e))_(a —X—(CR) ^(d)R^(e))_(b)—, phenylene,C₃₋₆cycloalkylidene or C₃₋₆cycloalkylene, wherein a and b are integers0-1 such that the sum of a and b equals 0, 1 or 2;

[0025] X is a bond, O, S, NR^(a), C(O), OC(O), C(O)O, C(O)NR^(a),OC(O)NR^(a), NR^(a)C(O), CR^(d)═CR^(e) or C≡C;

[0026] Y² is CR^(d)R^(e), CR^(d)R^(e)—CR^(d)R^(e), or CR^(d)═CR^(e),

[0027] R^(a) and R^(b) are independently selected from H, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, Cy and Cy C₁₋₁₀alkyl, wherein alkyl,alkenyl, alkynyl and Cy are optionally substituted with one to sixsubstituents independently selected from halogen, amino, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, aryl, heteroaryl, aryl C₁₋₄alkyl, hydroxy, CF₃,OC(O)C₁₋₄alkyl, OC(O)NR^(i)R^(j), and aryloxy; or

[0028] R^(a) and R^(b) together with the atom(s) to which they areattached form a heterocyclic ring of 4 to 7 members containing 0-2additional heteroatoms independently selected from oxygen, sulfur andN—R^(f);

[0029] R^(c) is selected from C₁₋₆alkyl optionally substituted with oneto six halogen, aryl and heteroaryl, wherein said aryl and heteroarylare optionally substituted with halogen,

[0030] OC₁₋₆alkyl, C₁₋₆alkyl and wherein said alkyl is optionallysubstituted with one to six halogen;

[0031] R^(d) and R^(e) are independently H, halogen, aryl, heteroaryl,C₁₋₆alkyl or haloC₁₋₆alkyl, or

[0032] R^(f) is selected from H, C₁₋₆alkyl, haloC₁₋₆alkyl, Cy,C(O)C₁₋₆alkyl, C(O)haloC₁₋₆ alkyl, and C(O)-Cy;

[0033] R^(g) is selected from

[0034] (1) halogen,

[0035] (2) CN,

[0036] (3) C₁₋₆alkyl optionally substituted with one to eight groupsindependently selected from aryl, heteroaryl, halogen, NR^(a)R^(b),C(O)R^(a), C(OR^(a))R^(a)R^(b), SR^(a) and OR^(a), wherein aryl,heteroaryl and alkyl are each optionally substituted with one to sixgroups independently selected from halogen, CF₃, and COOH,

[0037] (4) C₂₋₆alkenyl optionally substituted with one to six groupsindependently selected from halogen and OR^(a),

[0038] (5) Cy

[0039] (6) C(O)R^(a),

[0040] (7) C(O)OR^(a),

[0041] (8) CONR^(a)R^(b),

[0042] (9) OCONR^(a)R^(b),

[0043] (10) OC₁₋₆alkyl, wherein alkyl is optionally substituted with oneto six substituents selected from halogen, aryl, heteroaryl, OH andOC(O)R^(a),

[0044] (11) O-aryl

[0045] (12) O-heteroaryl

[0046] (13) S(O)_(n)C₁₋₆alkyl, wherein alkyl is optionally substitutedwith one to six substituents selected from halogen, aryl, heteroaryl,OH, and OC(O)R^(a),

[0047] (14) S(O)_(n)aryl,

[0048] (15) S(O)_(n)heteroaryl,

[0049] (16) —NR^(a)S(O)_(n)R^(b),

[0050] (17) —NR^(a)R^(b),

[0051] (18) —NR^(a)C(O)R^(b),

[0052] (19) —NR^(a)C(O)OR^(b),

[0053] (20) —NR^(a)C(O)NR^(a)R^(b),

[0054] (21) S(O)_(n)NR^(a)R^(b),

[0055] (22) NO₂,

[0056] (23) C₅₋₈cycloalkenyl,

[0057] wherein Cy is optionally substituted with one to eight groupsindependently selected from halogen, C(O)R^(a), OR^(a), C₁₋₃alkyl, aryl,heteroaryl and CF₃;

[0058] R^(i) and R^(j) are independently selected from hydrogen,C₁₋₁₀alkyl, Cy and Cy-C₁₋₁₀alkyl; or

[0059] R^(i) and R^(j) together with the carbon to which they areattached form a ring of 5 to 7 members containing 0-2 heteroatomsindependently selected from oxygen, sulfur and nitrogen;

[0060] Cy is selected from heterocyclyl, aryl, and heteroaryl;

[0061] n is 0, 1 or 2.

[0062] The invention also encompasses pharmaceutical compositionscontaining a compound of formula I, and methods for treatment orprevention of prostaglandin mediated diseases using compounds of formulaI.

[0063] The invention is described using the following definitions unlessotherwise indicated.

[0064] The term “halogen” or “halo” includes F, Cl, Br, and I.

[0065] The term “alkyl” refers to linear, branched and cyclic andbicyclic structures and combinations thereof, containing the indicatednumber of atoms. Non-limiting examples of alkyl groups include methyl,ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl, heptyl,octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl,eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylnonyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl,cyclopentylethyl, methyl substituted cyclopropyl, ethyl substitutedcyclobutyl, adamantyl cyclododecylmethyl, 2-ethyl-1-bicyclo[4.4.0]decyland the like. For example, the term C₁₋₆alkyl encompasses acyclic alkylgroups having the indicated number of carbon atoms as well as—C_(x)alkyl-C_(z)cycloalkyl wherein x is 0 to 3 and z is 3 to 6 with theproviso that x+z=3 to 6.

[0066] “Cycloalkylidene” refers to the following bivalent radical wherethe points of attachement are on the same carbon atom:

[0067] “Cycloalkylene” refers to the following bivalent radical wherethe points of attachment are on different carbon atoms:

[0068] “Thenylene” refers to the following bivalent radical and includes1,2-phenylene, 1,3-phenylene and 1,4-phenylene:

[0069] “Haloalkyl” means an alkyl group as described above wherein oneor more hydrogen atoms have been replaced by halogen atoms, with up tocomplete substitution of all hydrogen atoms with halo groups.C₁₋₆haloalkyl, for example, includes —CF₃, —CH₂CF₃, —CF₂CF₃ and thelike.

[0070] “Alkoxy” means alkoxy groups of a straight, branched or cyclicconfiguration having the indicated number of carbon atoms. C₁₋₆alkoxy,for example, includes methoxy, ethoxy, propoxy, isopropoxy, and thelike.

[0071] “Haloalkoxy” means an alkoxy group as described above in whichone or more hydrogen atoms have been replaced by halogen atoms, with upto complete substitution of all hydrogen atoms with halo groups.C₁₋₆haloalkoxy, for example, includes —OCF₃, —OCH₂CF₃, —OCF₂CF₃ and thelike.

[0072] “Alkenyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon double bond, wherein hydrogen may be replaced by anadditional carbon-to-carbon double bond. C₂₋₆alkenyl, for example,includes ethenyl, propenyl, 1-methyl-ethenyl, butenyl and the like.

[0073] “Heterocyclyl” refers to a non-aromatic ring having 1 to 4heteroatoms said ring being isolated or fused to a second ring selectedfrom 3- to 7-membered alicyclic ring containing 0 to 4 heteroatoms, aryland heteroaryl, wherein said heteroatoms are independently selected fromO, N and S. Non-limiting examples of heterocyclyl include oxetanyl,1,3-dithiacyclopentane, dihydrobenzoflran, and the like.

[0074] “Aryl” means a 6-14 membered carbocyclic aromatic ring systemcomprising 1-3 benzene rings. If two or more aromatic rings are present,then the rings are fused together, so that adjacent rings share a commonbond. Examples include phenyl and naphthyl.

[0075] The term “heteroaryl” (Het) as used herein represents a 5-10membered aromatic ring system containing one ring or two fused rings,1-4 heteroatoms, selected from O, S and N. Het includes, but is notlimited to, tetrazolyl, benzothienyl, quinolinyl, benzothiazolyl,furanyl, diazinyl, imidazolyl, isooxazolyl, isothiazolyl, oxadiazolyl,oxazolyl, pyrazolyl, pyridyl, pyrrolyl, tetrazinyl, thiazolyl,thiadiazolyl, thienyl, triazinyl, triazolyl, 1H-pyrrole-2,5-dionyl,2-pyrone, 4-pyrone, pyrrolopyridine, furopyridine and thienopyridine.

[0076] “Therapeutically effective amount” means that amount of a drug orpharmaceutical agent that will elicit the biological or medical responseof a tissue, a system, animal or human that is being sought by aresearcher, veterinarian, medical doctor or other clinician.

[0077] The term “treatment” or “treating” includes alleviating,ameliorating, relieving or otherwise reducing the signs and symptomsassociated with a disease or disorder.

[0078] The term “prophylaxis” means preventing or delaying the onset orthe progression of a disease or disorder, or the signs and symptomsassociated with such disease or disorder.

[0079] The term “composition”, as in pharmaceutical composition, isintended to encompass a product comprising the active ingredient(s), andthe inert ingredient(s) (pharmaceutically acceptable excipients) thatmake up the carrier, as well as any product which results, directly orindirectly, from combination, complexation or aggregation of any two ormore of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of Formula I, and pharmaceutically acceptable excipients.

[0080] For purposes of this specification, the following abbreviationshave the indicated meanings: Ac = acetyl AcO = acetate BOC =t-butyloxycarbonyl CBZ = carbobenzoxy CDI = carbonyldiimidazole DCC =1,3-dicyclohexylcarbodiimide DCE = 1,2-dichloroethane DIBAL = diisobutylaluminum hydride DIEA = N,N-diisoproylethylamine DMAP =4-(dimethylamino)pyridine DMF = dimethylformamide EDCI =1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDTA =ethylenediaminetetraacetic acid, tetrasodium salt hydrate FAB = fastatom bombardment EMOC = 9-fluorenylmethoxycarbonyl HMPA =hexamethylphosphoramide HATU = O-(7-Azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate HOBt = 1-hydroxybenzotriazoleHRMS = high resolution mass spectrometry ICBF = isobutyl chloroformateKHMDS = potassium hexamethyldisilazane LDA = lithium diisopropylamideMCPBA = metachloroperbenzoic acid MMPP = magnesium monoperoxyphthlatehexahydrate Ms = methanesulfonyl = mesyl MsO = methanefulfonate =mesylate NBS = N-bromosuccinimide NMM = 4-methylmorpholine NMP =N-methylpyrrolidinone PCC = pyridinium chlorochromate PDC = pyridiniumdichromate Ph = phenyl PPTS = pyridinium p-toluene sulfonate pTSA =p-toluene sulfonic acid PyH.Br₃ = pyridine hydrobromide perbromider.t./RT = room temperature rac. = racemic TFA = trifluoroacetic acid TfO= trifluoromethanesulfonate = triflate THF = tetrahydrofuran TLC = thinlayer chromatography TMSCl = trimethylsilyl chloride

[0081] Alkyl Group Abbreviations Me = methyl Et = ethyl n-Pr = normalpropyl i-Pr = isopropyl c-Pr = cyclopropyl n-Bu = normal butyl i-Bu =isobutyl c-Bu = cyclobutyl s-Bu = secondary butyl t-Bu = tertiary butyl

[0082] Compounds of the present invention have either one of the twofollowing tricyclic core structures, shown below with their numberingsystem used herein:

[0083] In one embodiment of formula I are compounds wherein Y¹ isselected from a bond, O, S, NR^(a), CHR^(d), CHR^(d)CHR^(d), C(O),C(O)CHR^(d), phenylene, and C₃₋₆cycloalkylidene. In one subset Y¹ isphenylene, S, C(O) or CH₂; in another subset Y¹ is S; in another subsetY¹ is C(O); in another subset Y¹ is CH₂. Examples of Y¹ include O, S,C(O), CH₂, CH₂CH₂, CH(CH₃), CH(CH₂CH₃)C(O)CH₂, 1,4-phenylene,1,3-phenylene, 1,1-cyclopropylidene, 1,4-cyclohexylene, NH, N(CH₃),N(CH₂CH₃), OC(O), C(O)O, C(O)NH, NHC(O), CH═CH, C≡C, and the like.

[0084] In another embodiment of formula I are compounds where Ar isnapthyl or phenyl each optionally substituted with one to three groupsindependently selected from R^(g). In one subset, Ar is 1-, or2-napthyl. In another subset Ar is phenyl optionally substituted withone to three groups independently selected from halogen, aryl,S(O)_(n)C₁₋₆alkyl optionally substituted with one to six halogen,C₁₋₆alkyl optionally substituted with one to five halogen atoms, CN,CONR^(a)R^(b), and C(O)R^(a), where R^(a) and R^(b) are as defined underformula I. In another subset, Ar is 4-chlorophenyl optionallysubstituted with a second halogen atom. Examples of Ar in thisembodiment include 1-naphthyl, 2-naphthyl, phenyl, 3-(n-butoxy)phenyl,4-chlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl,2,6-dichlorophenyl, 2,4,6-trichlorophenyl, 2,4,5-trichlorophenyl, 2-, 3-or 4-biphenyl, 4-chloro-2-(methylsulfonyl)phenyl,4-chloro-2-(carboxamido)phenyl, 2-cyano-4-chlorophenyl,4-chloro-2-iodophenyl, 4-(trifluoromethyl)phenyl,4-(methylsulfonyl)phenyl, 4-chloro-2-fluorophenyl,2-chloro-4-fluorophenyl, 2,3,4-trichlorophenyl, 2-chloro-4-cyanophenyl,4-acetyl-2-chlorophenyl, 3-chloro-4-acetylphenyl,2-bromo-4-chlorophenyl, 3-bromo-4-chlorophenyl, 4-bromo-2-chlorophenyl,2-fluoro-4-bromophenyl, 4-cyanophenyl,2-chloro-4-(trifluoromethyl)phenyl, and the like.

[0085] In another embodiment of formula I are compounds wherein Ar is aheteroaryl selected from furyl, pyridyl, benzothiazolyl, quinolinyl andpyrimidinyl, each optionally substituted with one or two halogen atoms.

[0086] In another embodiment of formula I are compounds wherein Y² isselected from CH₂ and CH₂CH₂. In one subset Y² is CH₂; in another subsetY² is CH₂CH₂. Examples of Y² include CH₂, CH₂CH₂, CH═CH, CHCl, CH₂CHCl,CCl₂, CCl₂—CCl₂, CH(CH₃), CH₂CH(Ph), C(Cl)═C(Cl), and the like.

[0087] In another embodiment of formula I are compounds wherein A isC₁₋₃alkyl optionally substituted with one to four halogen atoms and Q isCOOH or tetrazolyl. In one subset A-Q is selected from CH₂COOH, CF₂COOHand CH(CH₃)COOH. In another subset A-Q is CH₂COOH. Examples of Aincludes CH₂, CH₂CH₂, CH(CH₃), CH(CH₃)₂, CHF, CHFCF₂, CHCl,1,1-cyclopropylidene, 1,2-cyclopropylene, and the like. Examples of Qinclude COOH, CONH₂, CONH(CH₃), SO₂NH₂, tetrazolyl, and the like.

[0088] In another embodiment of formula I are compounds wherein R¹, R²and R³ are independently selected from hydrogen, CN, halogen,S(O)_(n)C₁₋₃alkyl, OC₁₋₆alkyl (optionally substituted with one to sixsubstituents selected from halogen, aryl, heteroaryl, OH andOC(O)R^(a)), C₁₋₆alkyl (optionally substitued with one to eight groupsselected from aryl, heteroaryl, halogen, NR^(a)R^(b), C(O)R^(a),C(OR^(a))R^(a)R^(b), SR^(a), and OR^(a), wherein aryl, heteroaryl andalkyl are each optionally substituted with one to six groupsindependently selected from halogen, CF₃, and COOH), aryl, heteroaryl,heterocyclyl, C₂₋₆alkenyl (optionally substituted with one to six groupsindependently selected from halogen and OR^(a)), C(O)OC₁₋₃alkyl,S(O)_(n)NR^(a)R^(b), C(O)R^(a), C(OH)R^(a)R^(b), C₅₋₈cycloalkenyl, andC(OC₁₋₃alkyl)R^(a)R^(b), wherein each of aryl, heteroaryl andheterocyclyl is optionally substituted with one to eight groupsindependently selected from halogen, C(O)R^(a), OR^(a), C₁₋₃alkyl, aryl,heteroaryl and CF₃; n=0, 1 or 2; R^(a) and R^(b) are independentlyselected from hydrogen and C₁₋₆alkyl optionally substituted withhalogen. Examples of R¹, R² and R³ include hydrogen, fluorine, chlorine,bromine, iodine, methylsulfonyl, ethylsulfonyl, methylsulfinyl, methoxy,isopropyloxy, methylthio, benzyloxy, acetyl, trifluoroacetyl,1-hydroxy-2,2,2-trifluoroethyl, 1-hydroxy-2-methylpropyl,1-hydroxyethyl, 1-methoxyethyl, 1-methoxypropyl,1-methoxy-2,2,2-trifluoroethyl, 1-hydroxypropyl, 1-methoxypropyl,1-methylthioethyl, ethyl, n-propyl, isopropyl, 3-pentyl, ethenyl,2-propenyl, 2-penten-3-yl, phenyl, 4-chlorophenyl, 2-methylphenyl,3-(1-pyrazolyl)phenyl, 2-methoxyphenyl, 3,4-dichlorophenyl, cyano, 1-and 2-methyltetrazole, 1-methyl-2-pyrrolyl, 1-methyl-5-pyrazolyl,2-thienyl, 3-methyl-2-thienyl, 3-thienyl, 4-methyl-3-thienyl,2-formyl-3-thienyl, 2-naphthyl, 3-pyridyl, 6- and 8-quinolinyl,3-benzothienyl, 3,5-dimethyl-4-isoxazolyl, cyclopropyl, cyclopentyl,cyclopentenyl, 2-hydroxy-1,1,1,3,3,3-hexafluoro-2-propyl,2-methoxy-1,1,1,3,3,3-hexafluoro-2-propyl, and the like. In one subsetR¹, R² and R³ are positioned as shown below in formula Ia, and all thevariables are as defined under formula I:

[0089] In one subgroup of formula Ia are compounds wherein R¹ ishydrogen. In another subgroup of formula Ia are compounds wherein R¹ ishydrogen, A-Q is CH₂COOH, and R² is selected from halogen,S(O)_(n)C₁₋₃alkyl, OC₁₋₆alkyl (optionally substituted with aryl), CN,C₂₋₆alkenyl, 1- and 2-methyltetrazolyl, 1-methylpyrrolyl and C₁₋₆alkyl.In another subgroup of formula Ia are compounds wherein R¹ is hydrogen,A-Q is CH₂COOH, and R³ is selected from halogen, S(O)_(n)C₁₋₃alkyl,OC₁₋₆alkyl, C(O)R^(a), C₁₋₆alkyl (optionally substitued with 3 to 6halogen atoms, and 0 or 1 group selected from OR^(a), SR^(a),),C₂₋₆alkenyl, C₅₋₈cycloalkenyl, phenyl (optionally substituted with agroup selected from C₁₋₃alkyl, OR^(a) and pyrazolyl), naphthyl, andheteroaryl selected from pyrrolyl, thienyl, pyrazolyl, quinolinyl,benzothienyl, isoxalyl, pyridyl, each of which is optionally substitutedwith C₁₋₃alkyl.

[0090] In another embodiment of formula I are compounds wherein R⁴ andR⁵ are each independently selected from H and C₁₋₄alkyl optionallysubstituted with one to six halogen atoms, preferably fluorine; or R⁴ isOR^(a) wherein R^(a) is as defined under formula I, preferably hydrogen;or R⁴ and R⁵ attached to the same carbon atom represent an oxo. In onesubset R⁴ and R⁵ are each hydrogen.

[0091] In a another embodiment of formula I are compounds of formula Ib:

[0092] wherein Ar and R¹-R⁵ are as defined under formula I and Y¹ is O,S, C(O) or CH₂. In one subset, R⁴ and R⁵ are each hydrogen, and R² andR³ represent one or two non-H substituent. In another subset of formulaIb are compounds of formula Ic:

[0093] wherein Y¹ is C(O), CH₂ or S, R and R′ are independentlyhydrogen, halogen, cyano, C₁₋₃alkanoyl or CF₃, and R² and R³ are each anon-hydrogen substituent. In one subgroup of formula Ic, R² is selectedfrom halogen, S(O)_(n)C₁₋₃alkyl, OC₁₋₆alkyl (optionally substituted witharyl), CN, C₂₋₆alkenyl, 1- or 2-methyltetrazolyl, 1-methylpyroolyl andC₁₋₆alkyl. In another subgroup of formula Ic, R³ is selected fromhalogen, S(O)_(n)C₁₋₃alkyl, OC₁₋₆alkyl, C(O)R^(a), C₁₋₆alkyl (optionallysubstitued with 3 to 6 halogen atoms, and 0 or 1 group selected fromOR^(a), SR^(a),), C₂₋₆alkenyl, C₅₋₈cycloalkenyl, phenyl (optionallysubstituted with a group selected from C₁₋₃alkyl, OR^(a) and pyrazolyl),naphthyl, and heteroaryl selected from pyrrolyl, thienyl, pyrazolyl,quinolinyl, benzothienyl, isoxalyl, pyridyl, each of which is optionallysubstituted with C₁₋₃alkyl. In another subgroup of formula Ic, R² is F,R is Cl and R′ is hydrogen or halogen. In another subgroup of formula Icare compounds where R² is F, R is Cl, R′ is hydrogen, and R³ is selectedfrom halogen, S(O)_(n)C₁₋₃alkyl, OC₁₋₆alkyl, C(O)R^(a), C₁₋₆alkyl(optionally substitued with 3 to 6 halogen atoms, and 0 or 1 groupselected from OR^(a), SR^(a),), C₂₋₆alkenyl, C₅₋₈cycloalkenyl, phenyl(optionally substituted with a group selected from C₁₋₃alkyl, OR^(a) andpyrazolyl), naphthyl, and heteroaryl selected from pyrrolyl, thienyl,pyrazolyl, quinolinyl, benzothienyl, isoxalyl, pyridyl, each of which isoptionally substituted with C₁₋₃alkyl.

[0094] Optical Isomers-Diastereomers-Geometric Isomers-Tautomers

[0095] Compounds of formula I contain one or more asymmetric centers andcan thus occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to comprehend all such isomeric forms of thecompounds of formula I.

[0096] Some of the compounds described herein contain olefinic doublebonds, and unless specified otherwise, are meant to include both E and Zgeometric isomers.

[0097] Some of the compounds described herein may exist with differentpoints of attachment of hydrogen, referred to as tautomers. Such anexample may be a ketone and its enol form known as keto-enol tautomers.The individual tautomers, as well as mixtures thereof, are encompassedwith compounds of formula I.

[0098] Compounds of the formula I may be separated intodiastereoisomeric pairs of enantiomers by, for example, fractionalcrystallization from a suitable solvent, for example methanol or ethylacetate or a mixture thereof. The pair of enantiomers thus obtained maybe separated into individual stereoisomers by conventional means, forexample by the use of an optically active acid as a resolving agent.

[0099] Alternatively, any enantiomer of a compound of the generalformula I or Ia may be obtained by stereospecific synthesis usingoptically pure starting materials or reagents of known configuration.

[0100] Salts

[0101] The term “pharmaceutically acceptable salts” refers to saltsprepared from pharmaceutically acceptable non-toxic bases includinginorganic bases and organic bases. Salts derived from inorganic basesinclude aluminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium; manganic salts, manganous, potassium, sodium, zinc, and thelike. Particularly preferred are the ammonium, calcium, magnesium,potassium, and sodium salts. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

[0102] When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids.

[0103] It will be understood that, unless otherwise specified,references to the compound of formula I are meant to also include thepharmaceutically acceptable salts.

[0104] Utilities

[0105] The ability of compounds of formula I to interact withprostaglandin receptors makes them useful for preventing or reversingundesirable symptoms caused by prostaglandins in a mammalian, especiallyhuman subject. This mimicking or antagonism of the actions ofprostaglandins indicates that the compounds and pharmaceuticalcompositions thereof are useful to treat, prevent, or ameliorate inmammals and especially in humans: respiratory conditions, allergicconditions, pain, inflammatory conditions, mucus secretion disorders,bone disorders, sleep disorders, fertility disorders, blood coagulationdisorders, trouble of the vision as well as immune and autoimmunediseases. In addition, such a compound may inhibit cellular neoplastictransformations and metastic tumor growth and hence can be used in thetreatment of cancer. Compounds of formula I may also be of use in thetreatment and/or prevention prostaglandin-mediated proliferationdisorders such as may occur in diabetic retinopathy and tumorangiogenesis. Compounds of formula I may also inhibit prostanoid-inducedsmooth muscle contraction by antagonizing contractile prostanoids ormimicking relaxing prostanoids and hence may be used in the treatment ofdysmenorrhea, premature labor and eosinophil related disorders. Moreparticularly compounds of formula I are antagonists of prostaglandin D2.

[0106] Accordingly, another aspect of the invention provides a method oftreating or preventing a prostaglandin mediated disease comprisingadministering to a mammalian patient in need of such treatment acompound of formula I in an amount which is effective for treating orpreventing said prostaglandin mediated disease. Prostaglandin mediateddiseases include, but are not limited to, allergic rhinitis, nasalcongestion, rhinorrhea, perennial rhinitis, nasal inflammation, asthmaincluding allergic asthma, chronic obstructive pulmonary diseases andother forms of lung inflammation; sleep disorders and sleep-wake cycledisorders; prostanoid-induced smooth muscle contraction associated withdysmenorrhea and premature labor; eosinophil related disorders;thrombosis; glaucoma and vision disorders; occlusive vascular diseases;congestive heart failure; diseases or conditions requiring a treatmentof anti-coagulation such as post-injury or post surgery treatment;inflammation; gangrene; Raynaud's disease; mucus secretion disordersincluding cytoprotection; pain and migraine; diseases requiring controlof bone formation and resorption such as for example osteoporosis;shock; thermal regulation including fever; and immune disorders orconditions in which immunoregulation is desirable. More particularly thedisease is to be treated is one mediated by prostaglandin D2 such asnasal congestion, pulmonary congestion, and asthma including allergicasthma.

[0107] In one embodiment of the invention is a method of treating orpreventing a prostaglandin mediated disease comprising administering toa mammalian patient in need of such treatment a compound of formula I inan amount which is effective for treating or preventing a prostaglandinmediated disease, wherein the prostaglandin mediated disease is nasalcongestion, rhinitis including allergic and perennial rhinitis, andasthma including allergic asthma.

[0108] In another embodiment of the present invention is a method oftreating or preventing a prostaglandin D2-mediated disease comprisingadministering to a mammalian patient in need of such treatment acompound of formula I in an amount which is effective for treating orpreventing a prostaglandin D2 mediated disease wherein saidprostaglandin D2 mediated disease is nasal congestion or asthma.

[0109] In another embodiment of the present invention is a method forthe treatment of nasal congestion in a patient in need of such treatmentwhich comprises administering to said patient a therapeuticallyeffective amount of a compound of formula I.

[0110] In yet another embodiment of the present invention is a methodfor the treatment of asthma, particularly allergic asthma, in a patientin need of such treatment which comprises administering to said patienta therapeutically effective amount of a compound of formula I.

[0111] In yet another embodiment of the present invention is a methodfor the treatment of allergic rhinitis, including seasonal allergicrhinitis and perennial allergic rhinitis, in a patient in need of suchtreatment which comprises administering to said patient atherapeutically effective amount of a compound of formula I.

[0112] Dose Ranges

[0113] The magnitude of prophylactic or therapeutic dose of a compoundof formula I will, of course, vary with the nature and the severity ofthe condition to be treated and with the particular compound of formulaI and its route of administration. It will also vary according to avariety of factors including the age, weight, general health, sex, diet,time of administration, rate of excretion, drug combination and responseof the individual patient. In general, the daily dose from about 0.001mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg toabout 10 mg per kg. On the other hand, it may be necessary to usedosages outside these limits in some cases.

[0114] The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Forexample, a formulation intended for the oral administration of humansmay contain from 0.05 mg to 5 g of active agent compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 99.95 percent of the total composition. Dosageunit forms will generally contain between from about 0.1 mg to about 0.4g of an active ingredient, typically 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25mg, 50 mg, 100 mg, 200 mg, or 400 mg.

[0115] Pharmaceutical Compositions

[0116] Another aspect of the present invention provides pharmaceuticalcompositions comprising a compound of formula I with a pharmaceuticallyacceptable carrier. The term “composition”, as in pharmaceuticalcomposition, is intended to encompass a product comprising the activeingredient(s), and the inert ingredient(s) (pharmaceutically acceptableexcipients) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of Formula I, additional activeingredient(s), and pharmaceutically acceptable excipients.

[0117] For the treatment of any of the prostanoid mediated diseasescompounds of formula I may be administered orally, by inhalation spray,topically, parenterally or rectally in dosage unit formulationscontaining conventional non-toxic pharmaceutically acceptable carriers,adjuvants and vehicles. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intrasternalinjection or infusion techniques. In addition to the treatment ofwarm-blooded animals such as mice, rats, horses, cattle, sheep, dogs,cats, etc., the compound of the invention is effective in the treatmentof humans.

[0118] The pharmaceutical compositions containing the active ingredientmay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavouringagents, colouring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example, magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the technique described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

[0119] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredients is mixed withwater-miscible solvents such as propylene glycol, PEGs and ethanol, oran oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0120] Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more colouringagents, one or more flavouring agents, and one or more sweeteningagents, such as sucrose, saccharin or aspartame.

[0121] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavouring agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

[0122] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavouring andcolouring agents, may also be present.

[0123] The pharmaceutical compositions of the invention may also be inthe form of an oil-in-water emulsion. The oily phase may be a vegetableoil, for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

[0124] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavouringand colouring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleagenous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butane diol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. Cosolvents such as ethanol, propylene glycol or polyethyleneglycols may also be used. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

[0125] Compounds of formula I may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ambient temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

[0126] For topical use, creams, ointments, gels, solutions orsuspensions, etc., containing the compound of formula I are employed.(For purposes of this application, topical application shall includemouth washes and gargles.) Topical formulations may generally becomprised of a pharmaceutical carrier, cosolvent, emulsifier,penetration enhancer, preservative system, and emollient.

[0127] Combinations with Other Drugs

[0128] For the treatment and prevention of prostaglandin mediateddiseases, compound of formula I may be co-administered with othertherapeutic agents. Thus in another aspect the present inventionprovides pharmaceutical compositions for treating prostaglandin mediateddiseases comprising a therapeutically effective amount of a compound offormula I and one or more other therapeutic agents. Suitable therapeuticagents for combination therapy with a compound of formula I include: (1)a prostaglandin D2 antagonist such as S-5751; (2) a corticosteroid suchas triamcinolone acetonide; (3) a β-agonist such as salmeterol,formoterol, terbutaline, metaproterenol, albuterol and the like; (4) aleukotriene modifier, including a leukotriene antagonist or alipooxygenase inhibitor such as montelukast, zafirlukast, pranlukast, orzileuton; (5) an antihistamine such as bromopheniramine,chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine,diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine,methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine,antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine,cetirizine, fexofenadine, descarboethoxyloratadine, and the like; (6) adecongestant including phenylephrine, phenylpropanolamine,pseudophedrine, oxymetazoline, ephinephrine, naphazoline,xylometazoline, propylhexedrine, or levo-desoxyephedrine; (7) anantiitussive including codeine, hydrocodone, caramiphen, carbetapentane,or dextramethorphan; (8) another prostaglandin ligand includingprostaglandin F agonist such as latanoprost; misoprostol, enprostil,rioprostil, omoprostol or rosaprostol; (9) a diuretic; (10)non-steroidal antiinflammatory agents (NSAIDs) such as propionic acidderivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen,fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen,ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen,suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives(indomethacin, acemetacin, alclofenac, clidanac, diclofenac,fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac,oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac),fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamicacid, niflumic acid and tolfenamic acid), biphenylcarboxylic acidderivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam,sudoxicam and tenoxican), salicylates (acetyl salicylic acid,sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone,mofebutazone, oxyphenbutazone, phenylbutazone); (11) cyclooxygenase-2(COX-2) inhibitors such as celecoxib and rofecoxib; (12) inhibitors ofphosphodiesterase type IV (PDE-A) e.g. Ariflo, roflumilast; (13)antagonists of the chemokine receptors, especially CCR-1, CCR-2, andCCR-3; (14) cholesterol lowering agents such as HMG-CoA reductaseinhibitors (lovastatin, simvastatin and pravastatin, fluvastatin,atorvastatin, and other statins), sequestrants (cholestyramine andcolestipol), nicotinic acid, fenofibric acid derivatives (gemfibrozil,clofibrat, fenofibrate and benzafibrate), and probucol; (15)anti-diabetic agents such as insulin, sulfonylureas, biguanides(metformin), α-glucosidase inhibitors (acarbose) and glitazones(troglitazone, pioglitazone, englitazone, rosiglitazone and the like);(16) preparations of interferon beta (interferon beta-1a, interferonbeta-1b); (17) anticholinergic agents such as muscarinic antagonists(ipratropium bromide and tiotropium bromide), as well as selectivemuscarinic M3 antagonists; (18) steroids such as beclomethasone,methylprednisolone, betamethasone, prednisone, dexamethasone, andhydrocortisone; (19) triptans commonly used for the treatment ofmigraine such as sumitriptan and rizatriptan; (20) alendronate and othertreatments for osteoporosis; (21) other compounds such as5-aminosalicylic acid and prodrugs thereof, antimetabolites such asazathioprine and 6-mercaptopurine, cytotoxic cancer chemotherapeuticagents, bradykinin (BK2) antagonists such as FK-3657, TP receptorantagonists such as seratrodast, neurokinin antagonists (NK1/NK2), VLA-4antagonists such as those described in U.S. Pat. No. 5,510,332,WO97/03094, WO97/02289, WO96/40781, WO96/22966, WO96/20216, WO96/01644,WO96/06108, WO95/15973 and WO96/31206. In addition, the inventionencompasses a method of treating prostaglandin D2 mediated diseasescomprising: administration to a patient in need of such treatment anon-toxic therapeutically effective amount of a compound of formula I,optionally co-administered with one or more of such ingredients aslisted immediately above.

[0129] Methods of Synthesis

[0130] Compounds of Formula I of the present invention can be preparedaccording to the synthetic routes outlined in Schemes 1 to 21 and byfollowing the methods described herein.

[0131] Method 1

[0132] Indole 1 can be alkylated with a halide at the 3-position to give2 under basic conditions. Compound 2 can be halogenated at the2-position to provide 3, which is alkylated with an approprate halide toyield 4. The acetal group in 4 can be hydrolyzed to give aldehyde 5.Wittig reaction of 5 with a phosphorane provides unsaturated ester 6.Under Heck coupling conditions, compound 6 cyclises to give 7.Hydrogenation of 7, followed by basic hydrolysis yields the finalproduct 9.

[0133] Method 2

[0134] Indole 1 can be sulphenylated with a disulfide at the 3-positionto give 10 under basic conditions. Compound 10 can be transformed to thefinal product 17 following the same sequences as described in Method 1.

[0135] Alternatively, the intermediate aldehyde 13 can be prepared bythe methods described in Scheme 3.

[0136] Method 3

[0137] Intermediate indole 25 may be prepared by the method presented inScheme 4. Benzaldehyde 18 is condensed with N₃CH₂CO₂Me under basicconditions to provide ester 19, which may be converted to indole 20 bythermolysis. Sulphenylation of indole 20 with ClSAr gives 21, which isthen alkylated with an appropriate bromo-ester to yield diester 22. Basepromoted cyclization of 22 affords keto-ester 23, which, upondecarboxylation, provides ketone 24. Wittig reaction of 24, followed byhydrogenation and hydrolysis, affords the final product 27.

[0138] The sequence in Scheme 4 can be altered as described in Scheme 5.The sulphenylation reaction can be conducted on compound 32, which maybe prepared from compound 20 under same conditions as described inScheme 4.

[0139] Alternatively, compound with six-membered ring can be preparedby, the sequence described in Scheme 6. Reformatsky reaction on 30provides alcohol 35a. Deoxygenation of 35a provides ester 32a, which isthen sulphenylated with ClSAr to provide 26. Basic hydrolysis of 26provides the target compound 27.

[0140] Compounds with five-membered ring may be prepared by the methodpresented in Scheme 7 from indole 20. Indole 20 is condensed with methylacrylate under basic conditions to provide keto-ester 33.Decarboxylation of 33, followed by Reformatsky reaction, providesalcohol 35. Deoxygenation of 35 provides ester 36, which is thensulphenylated with ClSAr to provide 37. Basic hydrolysis of 37 providesthe target compound 38.

[0141] If R¹, R² or R³═X (X could be: Cl, Br, I, OTf), then alkylmethanesulfonyl, cyano, aryl, heteroaryl and heterocycle could beintroduced on the indole scaffold by metal-catalyzed cross-couplingreactions on 36a and/or 36c as described in Scheme. 8.

[0142] For compounds where X is a Br or I atom, metal halogen exchangeon 36e and 36g could be done and the resulting organometallic speciescould be added to an electrophile such as alkyl disulfides and aldehydesas described in Scheme 9.

[0143] Method 4

[0144] Compounds with an aryl group directly attached to the 3-positionof indole such as 43 can be synthesized according the sequence describedin Scheme 10. The intermediate indole 41 may be prepared from aniline 39and an α-substituted acetoacetate 40. Decarboxylation of 41 providesindole 42, which can then be converted to the target compound 43 byfollowing the sequences described in Scheme 1-3.

[0145] Compounds with an aryl group directly attached to the 3-positionof indole such as 43 can also be synthesized according the sequencedescribed in Scheme 11. Indole 36i is brominated with NBS to provide thebromo indole 36j which under Suzuki coupling condition can afford thearyl indole 36k. Basic hydrolysis of 36k provided the target compound36l.

[0146] Method 5

[0147] 3-Substituted indole 2 can also be prepared by the methoddepicted in Scheme 12. Indole 1 can be silylated with a trialkylsilylhalide under basic conditions to give silylated indole 44. Brominationof 44 provides 45, which may be lithiated with alkyllithium andalkylated with an appropriate halide to afford 3-substituted indole 2.

[0148] Method 6

[0149] The compounds substituted with a variety of alkoxy, aryloxy orheteroaryloxy at the 6-positions of the indole structure can besynthesized according to the reaction sequence depicted in Scheme 13.Intermediate 47 can be prepared by the methods described in Method 3.Methylsulfonylation and demethylation of 47 provide phenol 48, which canreact with a variety of alkyl halides, aryl halides or heteroarylhalides and a base to yield 49. Sulphenylation and hydrolysis under thereaction conditions described in Method 3 may afford the final compound50.

[0150] Method 7

[0151] Intermediate 47 can be transformed to trifluoromethanesulfonate51. Sulphenylation of 51 provides compound 52 (Scheme 14), which can besubjected to transition metal catalyzed cross coupling reactions toyield the 6-aryl substituted compound 53 after basic hydrolysis.

[0152] Method 8

[0153] The compounds substituted with a variety of alkyl, alkenyl oraryl at the 8-positions of the indole structure can be synthesizedaccording to the reaction sequence depicted in Scheme 15. Intermediate54 can be prepared by the methods described in Method 3. Transitionmetal catalyzed cross coupling reaction of 54 with a organometallicreagent RM(R=alkyl, alkenyl, alkynyl or aryl and M=—B(OH)₂, —SnBu₃,—ZnCl or —ZnBr) affords 55 which can be converted to the final productby following the reaction conditions described in Method 3, 6 and 7.

[0154] Method 9

[0155] 3-substituted methylene indole can be prepared by using thesequence described in Scheme 16. Indole 36i is alkylated under acidiccondition to give 3-substituted indole 55 which is hydrolyzed underbasic condition to afford 56.

[0156] Method 10

[0157] 3-carbonyl indole can be prepared by using the sequence describedin Scheme 17. Indole 36i is acylated under Friedel-Craft condition togive 3-carbonyl indole 57 which is hydrolyzed under basic condition toafford 58.

[0158] Method 11

[0159] 3-alpha methyl indole can be prepared by using the sequencedescribed in Scheme 18. Acid 58 is esterified to the t-Butyl ester 59which after Wittig olefination gives the vinyl indole 60. The vinylgroup of indole 60 is reduced by hydrogenation with Pd/C to give 61which is hydrolyzed under acidic condition with TFA to afford 62.

[0160] Method 12

[0161] Oxo pyrrolo indole can be prepared by using the sequencedescribed in Scheme 19. The indole 20 was reduced to the alcohol 63 withDIBAL. Oxidation of 63 with Dess-Martin periodinane gives the aldehyde64 which can be converted to unsaturated ester 65 after Wittig reactionwith a phosphorane. Addition of the anion of diethyl malonate tounsaturated ester 65 and decarboxylation of the resulting indole 66gives 67. The indole 67 is sulphenylated with ClSAr to give 68 which ishydrolyzed under acidic condition to give the target compound 69.

[0162] If R³═X (X could be: Cl, Br, I, OTf) alkyl group, methanesulfonyl, heteroaryl and heterocycle could be introduced on the indolescaffold by metal-catalyzed cross-coupling reactions on 68a to yield 69aas described in Scheme 20.

[0163] Method 13

[0164] 6-Hydroxy indole derivative 48 can be converted into triflate 70,which is subjected to a transition metal catalyzed coupling reactionwith i-Pr₃SiSK to give 71. Desilylation of 71 followed by alkylationwith R^(a)X can provide 72. Sulphenylation reaction of 72 and aqueoushydrolysis yield the desired product 73.

[0165] Representative Compounds

[0166] Representative compounds of formula I are shown in the followingTables. Each entry is intended to include the racemic or diastereomericmixture, and the individual enantiomers and/or diastereomers. Methodsfor the resolution of enantiomers and for the separation ofdiastereomers are well known to those skilled in the art; selectiveillustration of such methods are also described in the Examples hereinbelow. TABLE I

Ex. R² R³ Y¹ Ar p 1 H H CH₂ 4-Cl—Ph 2 2 H H CH₂ 4-Cl—Ph 1 3 H H S4-Cl—Ph 2 4 CH₃S(O)₂ H S 4-Cl—Ph 2 5 H CH₃S(O) — 4-Cl—Ph 2 6 H CH₃S(O)CH₂ 4-Cl—Ph 2 7 F Br S 4-Cl—Ph 1 8 F Br S 4-Cl—Ph 2 9 CH₃S(O)₂ CH₃O S4-Cl—Ph 2 10 F CH₃C(O) S 4-Cl—Ph 1 11 F CF₃C(O) S 4-Cl—Ph 1 12 pCF₃CH(OH) S 4-Cl—Ph 1 13 F (CH₃)₂CHCH(OH) S 4-Cl—Ph 1 14 F CH₃CH(OH) S4-Cl—Ph 1 15 F CH₃CH(OCH₃) S 4-Cl—Ph 1 16 F CH₃C(O) S Ph 1 17 F CH3C(O)S 3,4-diCl—Ph 1 18 F CF3CH(OCH3) S 4-Cl—Ph 1 19 F CH3CH2CH(OH) S 4-Cl—Ph1 20 F CH3CH2CH(OCH3) S 4-Cl—Ph 1 21 F CH3CH(SCH3) S 4-Cl—Ph 1 22 CH₃OCH₃S(O)₂ S 4-Cl—Ph 1 23 PhCH₂O CH₃S(O)₂ S 4-Cl—Ph 1 24 CH₃S CH₃S(O)₂ S4-Cl—Ph 1 25 CH₃S(O)₂ (CH₃)₂CH S 4-Cl—Ph 1 26 (CH₃)₂CHO CH₃S(O)₂ S4-Cl—Ph 1 27 PhCH₂O (CH₃)₂CH S 4-Cl—Ph 1 28 CH₃O (CH₃)₂CH S 4-Cl—Ph 1 294-Cl-Ph CH₃S(O)₂ S 4-Cl—Ph 1 30 I Br S 4-Cl—Ph 1 31 CN Br S 4-Cl—Ph 1 322-CH₃-5-Tz# Br S 4-Cl—Ph 1 33 1-CH₃-5-Tz Br S 4-Cl—Ph 1 341-CH₃-2-pyrrolyl Br S 4-Cl—Ph 1 35 CN CH₃C(O) S 4-Cl—Ph 1 36 2-CH₃-5-TzCH₃C(O) S 4-Cl—Ph 1 37 F CH₃S(O)₂ S 4-Cl—Ph 1 38 F CH₃CH₂S(O)₂ S 4-Cl—Ph1 39 F 1-CH₃-2-pyrrolyl S 4-Cl—Ph 1 40 F CH₃CH₂CH₂ S 4-Cl—Ph 1 41 FCH₃CH₂ S 4-Cl—Ph 1 42 F CH₃C(═CH₂) S 4-Cl—Ph 1 43 F 1-CH₃-5-pyrazolyl S4-Cl—Ph 1 44 F (CH₃)₂CH S 4-Cl—Ph 1 45 F 1-cyclopentenyl S 4-Cl—Ph 1 46F (CH₃CH═)(CH₃CH₂)C S 4-Cl—Ph 1 47 F (CH₃CH₂)₂CH S 4-Cl—Ph 1 48 Fcyclopentyl S 4-Cl—Ph 1 49 F Ph S 4-Cl—Ph 1 50 F 2-thienyl S 4-Cl—Ph 151 F 3-CH₃-2-thienyl S 4-Cl—Ph 1 52 F CH₂═CH S 4-Cl—Ph 1 53 CH₂═CH Br S4-Cl—Ph 1 54 F (CF₃)₂C(OH) S 4-Cl—Ph 1 55 F 3-thienyl S 4-Cl—Ph 1 56cyclopropyl 1-CH₃-2-pyrrolyl S 4-Cl—Ph 1 57 2-CH₃-5-Tz 1-CH3-2-pyrrolylS 4-Cl—Ph 1 58 2-CH₃-5-Tz Ph S 4-Cl—Ph 1 59 F cyclopropyl S 4-Cl—Ph 1 60F Br CH₂ 4-Cl—Ph 1 61 F CH₃S(O)₂ CO 4-Cl—Ph 1 62 F CH₃S(O)₂ CH₂ 4-Cl—Ph1 63 F (CF₃)₂C(OCH₃) S 4-Cl—Ph 1 64 F (CH₃)₂CH C(O) 4-Cl—Ph 1 65 F1-CH₃-2-pyrrolyl C(O) 4-Cl—Ph 1 66 F (CH₃)₂CH CH₂ 4-Cl—Ph 1 67 FCH₃S(O)₂ CH₂ 2,4-diCl—Ph 1 68 F CH₃S(O)₂ CH₂ 2,6-diCl—Ph 1 69 F Br C(O)4-Cl—Ph 1 70 F cyclopropyl C(O) 4-Cl—Ph 1 71 F (CH₃O)(CH₃CH₂)CH C(O)4-Cl—Ph 1 72 F Ph C(O) 4-Cl—Ph 1 73 F 2-thienyl C(O) 4-Cl—Ph 1 74 FCH₃S(O)₂ CH₂ 2,4,6-triCl—Ph 1 75 F CH₃S(O)₂ S 2,4,5-triCl—Ph 1 76 FCH₃S(O)₂ C(O) 4-biphenyl 1 77 F CH₃S(O)₂ C(O) 2-naphthyl 1 78 F Br C(O)2-naphthyl 1 79* F CH₃S(O)₂ S 4-Cl—Ph 1 80 F CH₃S(O)₂ C(O) 2-furyl 1 81F CH₃S(O)₂ C(O) 2,4-diCl—Ph 1 82 F CH₃S(O)₂ C(O) 4-Cl-2-CH₃S(O)₂-Ph 1 83F Br C(O) 4-Cl-2-I—Ph 1 84 F Br C(O) 4-Cl-2-CONH₂-Ph 1 85 F CH₃S(O)₂C(O) 4-Cl-2-CN—Ph 1 86 F (CH₃)₂CH C(O) 4-Cl-2-I—Ph 1 87 F Br C(O)2-benzothia-zolyl 1 88 F (CH₃)₂CH C(O) 4-Cl-2-CH₃S(O)₂-Ph 1 89 FCH₃S(O)₂ S 4-CF₃—Ph 1 90 F CH₃S(O)₂ S 4-CH₃S(O)₂—Ph 1 91 F Br C(O)2-guinolinyl 1 92 F CH₃S(O)₂ C(O) 2-guinolinyl 1 93 F Br S2-benzothiazolyl 1 94 F CH₃S(O)₂ S 2-benzothiazolyl 1 95 2-CH₃-5-TzCH₃S(O)₂ S 4-Cl—Ph 1 96 F CH₃S(O)₂ CH(CH₃) 4-Cl—Ph 1. 97** F CH₃S(O)₂C(O)CH₂ 4-Cl—Ph 1 98 F (CH₃)₂CH S 1-naphthyl 1 99 F (CH₃)₂CH S2-naphthyl 1 100 F Br S 2-pyrimidinyl 1 101 F CH₃S(O)₂ S 2-pyrimidinyl 1102 F CH₃S(O)₂ CH₂CH₂ 4-Cl—Ph 1 103 2-CH₃-5-Tz (CH₃O)(CH₃CH₂)CH S4-Cl—Ph 1 104 F (CH₃)₂CH C(O) 2-naphthyl 1 105 F CH₃S(O)₂ S 2-naphthyl 1106 F (CH₃)₂CH S 4-Cl-2-F—Ph 1 107 F CH₃S(O)₂ S 4-Cl-2-F—Ph 1 108 F2-CH₃—Ph S 4-Cl—Ph 1 109 F 8-guinolinyl S 4-Cl—Ph 1 110 F 3-benzothienylS 4-Cl—Ph 1 111 F 3,5-diCH₃-4-isoxalyl S 4-Cl—Ph 1 112 F 4-CH₃-3-thienylS 4-Cl—Ph 1 113 F 3-(1-pyrazolyl)-Ph S 4-Cl—Ph 1 114 F2-(HC(O))-3-tbienyl S 4-Cl-Ph 1 115 F 2-OCH3-Ph S 4-Cl-Ph 1 116 F3,4-diCl-Ph S 4-Cl-Ph 1 117 F 6-gumolmyl S 4-Cl-Ph 1 118 F 2-naphthyl S4-Cl-Ph 1 119 F CN S 4-Cl-Ph 1 120 F (CH₃)₂CH C(O) 1-naphthyl 1 121 F(CH₃)₂CH C(O) 3,4-diCl—Ph 1 122 F (CH₃)₂CH S 4-Cl—Ph 2 123 F (CH₃)₂CHC(O) 2-naphthyl 2 124 F (CH₃)₂CH C(O) 4-Cl—Ph 2 125 F CH₃S(O)₂ S 4-Cl—Ph2 126 F CH₃S(O)₂ 1,4-phenylene Ph 1 127 F CH₃S(O)₂ — 2-naphthyl I 128 FCH₃S(O)₂ 1,3-phenylene Ph 1 129 CN (CH₃)₂CH S 4-Cl—Ph 1 130 2-CH₃-5-Tz(CH₃)₂CH S 4-Cl—Ph 1 131 1-CH₃-5-Tz (CH₃)₂CH S 4-Cl—Ph 1 132 CH₃S(O)₂CH₃S(O)₂ S 4-Cl—Ph 1 133 H 1-CH₃-2-pyrrolyl S 4-Cl—Ph 1 134 F 3-pyridylS 4-Cl—Ph 1 144 F CH₃S(O)₂ C(O) 4-Cl—Ph 2 145 F CH₃S(O)₂ C(O) 2-naphthyl2 146 F (CH₃)₂CH C(O) 3-Br-4-Cl—Ph 2 147 F (CH₃)₂CH CH₂ 4-Cl—Ph 2 148 F(CH₃)₂CH S 3-Br-4-Cl—Ph 2 149 F (CH₃)(CH₂═)C C(O) 4-Cl—Ph 2 150 FCH₃S(O)₂ C(O) 6-Cl-Pyr## 2 151 F CH₃S(O)₂ C(O) 3,4-diCl—Ph 2 152 FCH₃S(O)₂ C(O) 4-nBu—Ph 2 153 F CH₃S(O)₂ C(O) 4-Ph—Ph 2 154 PhCH₂OCH₃S(O)₂ S 4-Cl—Ph 2 155 PhCH₂S CH₃S(O)₂ S 4-Cl—Ph 1 156 F CH₃S(O)₂ C(O)4-Cl—Ph 2

[0167] TABLE II

Ex. R¹ R² R³ A—Q 135 F F 1-CH₃-2- CH₂CO₂H pyrrolyl 136 F F CH₃S(O)₂CH₂CO₂H 137 F F S-(4-Cl-Ph) CH₂CO₂H 138 CH₃S(O)₂ F CH₃S(O)₂ CH₂CO₂H 139CH₃S(O)₂ CH₃O CH₃S(O)₂ CH₂CO₂H 140 F H CH₃S(O)₂ CH₂CO₂H 141 H F BrCF₂CO₂H  142* H F Br CF₂CO₂H 143 H F CH₃S(O)₂ CF₂CO₂H

[0168] TABLE III

R¹/R² R³ A—Q/R⁶ Y¹ Ar H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 4-Cl-phe H/SO₂MeCH(OH)CH₃ CH₂CO₂H CH₂ 4-Cl-phe H/SO₂Me Br CH₂CO₂H CH₂ 2,4-Cl₂phe H/SO₂MeCH═CH₂ CH₂CO₂H O 4-Cl-phe H/SO₂Me c-pr CH₂CO₂H O 4-Cl-phe H/SO₂Methiophen-2-yl CH₂CO₂H S 4-Cl-phe H/SO₂NMe₂ H CH₂CO₂H S 4-Cl-phe H/F BrCH₂CO₂H/CH₃ S 4-Cl-phe H/Br H CH₂CO₂H S 4-Cl-phe H/CN C(O)CH₃ CH₂CO₂H S2,4-Cl₂-phe H/CN H CH₂CO₂H S 3,4-Cl₂-phe H/CN H CH₂CO₂H O 4-Cl-pheH/5-methyl-1,2,4-oxadiazol-3-yl H CH₂CO₂H CO 2,4-Cl₂-pheH/3-methyl-1,2,4-oxadiazol-3-yl H CH₂CO₂H CO 3,4-Cl₂-pheH/2-methyl-2H-tetrazol-5-yl H CH₂CO₂H CO 4-Cl-pheH/5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl H CH₂CO₂H 2,4-Cl₂-phe H/CF₃ HCH₂CO₂H CH₂ 3,4-Cl₂-phe H/CF₃ H CH₂CO₂H CHCH₃ 3,4-Cl₂-phe H/CF₃ HCH₂CO₂H CH₂ 4-Cl-phe H/F H CH(CH₃)CO₂H S 2,4-Cl₂-phe H/F H CH₂CO₂H CH₂2,4-Cl₂-phe H/3-methyl-1,2,4-thiadiazol-5-yl H CH₂CO₂H S 3,4-Cl₂-phe H/FH CH₂CO₂H NH 4-Cl-phe H/F H CH₂CO₂H CH₂ 2-Cl-4-F—pheH/4-methyl-1,3-thiazol-2-yl H CH₂CO₂H O 2-F-4-Cl—phe H/F H CH₂CO₂H1,1-cPr 4-Cl-phe H/F H CH₂CO₂H CH₂ 2,4,6-Cl₃-phe H/F H CH₂CO₂H S2,3,4-Cl₃-phe H/H F CH₂CO₂H CH₂ 2-Cl-4-CN-phe H/F H CH₂CO₂H CH₂ 4-CN-pheH/F H CH₂CO₂H CH₂ 4-COCH₃-phe H/F H CH₂CO₂H CH₂ 3-Cl-4-CN-phe H/F HCH₂CO₂H CH₂ 3-Cl-4-COCH₃-phe H/F 4-F-Phe CH₂CO₂H CH₂ 4-CF₃-phe H/F1-methyl-1H-pyrrol-2-yl CH₂CO₂H S 2-Cl-4-CF₃-phe H/F H CH₂CO₂H S3-Cl-4-CF₃-phe H/F H CH₂CO₂H O 2,6-Cl₂-phe H/F H CH₂CO₂H CH₂2,4,6-F₃-phe H/F CO₂Me CH(CH₃)CO₂H CH₂ 2,4-Cl₂-phe H/F CO₂Me CH₂CO₂H CH₂2,4-Cl₂-phe H/F CO₂Me CH₂CO₂H S 3,4-Cl₂-phe H/F CO₂Me CH₂CO₂H CH₂4-Cl-phe H/F CO₂Me CH₂CO₂H CH₂ 2-Cl-4-F-phe H/F CO₂Me CH₂CO₂H O2-F-4-Cl-phe H/F CO₂Me CH₂CO₂H 1,1-c-pr 4-Cl-phe H/F CO₂Me CH₂CO₂H CH₂2,4,6-Cl₃-phe H/F CO₂Me CH₂CO₂H S 2,3,4-Cl₃-phe H/F CO₂Me CH₂CO₂H CH₂2-Br-4-Cl-phe H/F CO₂Me CH₂CO₂H CH₂ 2-Cl-4-Br-phe H/F CO₂Me CH₂CO₂H NH2-F-4-Br-phe H/F CO₂Me CH₂CO₂H NMe 2-Cl-4-CN-phe H/F CO₂Me CH₂CO₂H CH₂2-Cl-4-COCH₃-phe H/F CO₂Me CH₂CO₂H CH₂ 4-CN-phe H/F CO₂Me CH₂CO₂H NEt4-COCH₃-phe H/F CO₂Me CH₂CO₂H CH₂ 3-Cl-4-CN-phe H/F CO₂Me CH₂CO₂H S3-Cl-4-COCH₃-phe H/F CO₂Me CH₂CO₂H CH₂ 4-CF₃-phe H/F CO₂Me CH₂CO₂H S2-Cl-4-CF₃-phe H/F CO₂Me CH₂CO₂H S 3-Cl-4-CF₃-phe H/F CO₂Me CH₂CO₂H O2,6-Cl₂-phe H/F CO₂Me CH₂CO₂H NH 2,4,6-F₃-phe H/F SOMe CH(CH₃)CO₂H CHMe2,4-Cl2-phe H/F SOMe CH₂CO₂H CH₂ 2,4-Cl₂-phe H/F SOMe CH₂CO₂H CH₂3,4-Cl₂-phe H/F SOMe CH₂CO₂H CH2 4-Cl-phe H/F SOMe CH₂CO₂H O2-Cl-4-F-phe H/F SOMe CH₂CO₂H CH₂ 2-F-4-Cl-phe H/F SOMe CH₂CO₂H 1,1-c-pr4-Cl-phe H/F SOMe CH₂CO₂H S 2,4,6-Cl₃-phe H/F SOMe CH₂CO₂H CH₂2,3,4-Cl₃-phe H/F SOMe CH₂CO₂H CH₂ 2-Br-4-Cl-phe H/F SOMe CH₂CO₂H CH₂2-Cl-4-Br-phe H/F SOMe CH₂CO₂H S 2-F-4-Br-phe H/F SOMe CH₂CO₂H CH₂2-Cl-4-CN-phe H/F SOMe CH₂CO₂H CH₂ 2-Cl-4-COCH₃-phe H/F SOMe CH₂CO₂H CH₂4-CN-phe H/F SOMe CH₂CO₂H CH₂ 4-COCH₃-phe H/F SOMe CH₂CO₂H S3-Cl-4-CN-phe H/F SOMe CH₂CO₂H CH₂ 3-Cl-4-COCH-phe H/F SOMe CH₂CO₂H O4-CF₃-phe H/F SOMe CH₂CO₂H CH₂ 2-Cl-4-CF₃-phe H/F SOMe CH₂CO₂H CH₂3-Cl-4-CF₃-phe H/F SOMe CH₂CO₂H NH 2,6-Cl₂-phe H/F SOMe CH₂CO₂H CH₂2,4,6-F₃-phe H/SO₂Me C(O)CH₃ CH₂CO₂H O 2,4-Cl₂-phe H/SO₂Me C(O)CH₃CH₂CO₂H CH₂ 3,4-Cl₂-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 2-Cl-4-F-phe H/SO₂MeC(O)CH₃ CH₂CO₂H CH₂ 2-F-4-Cl-phe H/SO₂Me C(O)CH₃ CH₂CO₂H 1,1-c-pr4-Cl-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 2,4,6-Cl₃-phe H/SO₂Me C(O)CH₃CH₂CO₂H CH₂ 2,3,4-Cl₃-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 2-Br-4-Cl-pheH/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 2-Cl-4-Br-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂2-F-4-Br-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 2-Cl-4-CN-phe H/SO₂Me C(O)CH₃CH₂CO₂H CH₂ 2-Cl-4-COCH₃-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 4-CN-pheH/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 4-COCH₃-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂3-Cl-4-CN-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 3-Cl-4-COCH₃-phe H/SO₂MeC(O)CH₃ CH₂CO₂H CH₂ 4-CF₃-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 2-Cl-4-CF₃-pheH/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 3-Cl-4-CF₃-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂2,6-Cl₂-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 2,4,6-F₃-phe H/SO₂MeCH(OR)CH₃CH(CH₃)CO₂H CH₂ 2,4-Cl₂-phe H/SO₂Me CH(OH)CH₃CH₂CO₂R O2,4-Cl₂-phe H/SO₂Me CH(OH)CH₃CH₂CO₂R CH₂ 3,4-Cl₂-phe H/SO₂MeCH(OH)CH₃CH₂CO₂R CH₂ 2-Cl-4-F-phe H/SO₂Me CH(OH)CH₃CH₂CO₂R CH₂2-F-4-Cl-phe H/SO₂Me CH(OH)CH₃ CH₂CO₂H 1,1-c-pr 4-Cl-phe H/SO₂MeCH(OH)CH₃ CH₂CO₂H CH₂ 2,4,6-Cl₃-phe H/SO₂Me CH(OH)CH₃ CH₂CO₂H CH₂2,3,4-Cl₃-phe H/SO₂Me CR(OH)CH₃ CH₂CO₂H CH₂ 2-Br-4-Cl-phe H/CH(OH)CH₃SO₂Me CH₂CO₂H CH₂ 2-Cl-4-Br-phe H/CH(OH)CH₃ SO₂Me CH₂CO₂H CH₂2-F-4-Br-phe H/CH(OH)CH₃ SO₂Me CH₂CO₂H CH₂ 2-Cl-4-CN-phe H/CH(OH)CH₃SO₂Me CH₂CO₂H CH₂ 2-Cl-4-COCH₃-phe H/CH(OH)CH₃ SO₂Me CH₂CO₂H CH₂4-CN-phe H/CH(OH)CH₃ SO₂Me CH₂CO₂H S 4-COCH₃-phe H/SO₂Me CH(OH)CH₃CH₂CO₂H CH₂ 3-Cl-4-CN-phe H/SO₂Me CH(OH)CH₃ CH₂CO₂H CH₂ 3-Cl-4-COCH₃-pheH/SO₂Me CH(OH)CH₃ CH₂CO₂H CH₂ 4-CF₃-phe H/SO₂Me CH(OH)CH₃ CH₂CO₂H CH₂2-Cl-4-CF₃-phe H/SO₂Me CH(OH)CH₃ CH₂CO₂H CH₂ 3-Cl-4-CF₃-phe H/SO₂MeCH(OH)CH₃ CH₂CO₂H CH₂ 2,6-Cl₂-phe H/CH(OR)CH₃ SO₂Me CH₂CO₂H S2,4,6-F₃-phe H/CO₂CH₃ SO₂Me CH(CH₃)CO₂H CH₂ 2,4-Cl₂-phe H/CO₂CH₃ SO₂MeCH₂CO₂H CH₂ 2,4-Cl₂-phe H/SO₂Me CO₂CH₃ CH₂CO₂H O 3,4-Cl₂-phe H/SO₂MeCO₂CH₃ CH₂CO₂H CH₂ 4-Cl-phe H/SO₂Me CO₂CH₃ CH₂CO₂H CH₂ 2-Cl-4-F-pheH/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2-F-4-Cl-phe H/CO₂CH₃ SO₂Me CH₂CO₂H 1,1-c-pr4-Cl-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2,4,6-Cl₃-phe H/CO₂CH₃ SO₂Me CH₂CO₂HCH₂ 2,3,4-Cl₃-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2-Br-4-Cl-phe H/CO₂CH₃SO₂Me CH₂CO₂H CH₂ 2-Cl-4-Br-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2-F-4-Br-pheH/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2-Cl-4-CN-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂2-Cl-4-COCH₃-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 4-CN-phe H/CO₂CH₃ SO₂MeCH₂CO₂H CH₂ 4-COCH₃-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 3-Cl-4-CN-pheH/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 3-Cl-4-COCH₃-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂4-CF₃-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2-Cl-4-CF₃-phe H/CO₂CH₃ SO₂MeCH₂CO₂H CH₂ 3-Cl-4-CF₃-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2,6-Cl₂-pheH/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2,4,6-F₃-phe H/CO₂CH₃ SO₂Me CH₂CO₂H S2,4-Cl₂-phe H/CO₂CH₃ SO₂Me CH₂CO₂H S 3,4-Cl₂-phe H/CO₂CH₃ SO₂Me CH₂CO₂HS 4-Cl-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2,4-Cl₂-phe H/CO₂CH₃ SO₂Me CH₂CO₂HCH₂ 3,4-Cl₂-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 4-Cl-phe H/CO₂CH₃ SO₂MeCH₂CO₂H CH₂ 2,4-Cl₂-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 3,4-Cl₂-phe H/CO₂CH₃SO₂Me CH₂CO₂H CH₂ 4-Cl-phe H/CO₂CH₃ SO₂Me CH₂CO₂H/CH₃ CH₂ 2,4-Cl₂-pheH/CO₂CH₃ SO₂Me CH₂CO₂H/CH₃ CH₂ 3,4-Cl₂-phe H/CO₂CH₃ SO₂Me CH₂CO₂H/CH₃CH₂ 4-Cl-phe H/SO₂Me CO₂CH₂CH₃ CH₂CO₂H CH₂ 3,4-Cl₂-phe H/SO₂Me CO₂CH₂CH₃CH₂CO₂H CH₂ 4-Cl-phe H/C(OH)(CH₂)₂SO₂Me CH₂CO₂H CH₂ 2,4-Cl₂-pheH/C(OH)(CH₂)₂SO₂Me CH₂CO₂H CH₂ 3,4-Cl₂-phe H/C(OH)(CH₂)₂SO₂Me CH₂CO₂HCH₂ 4-Cl-phe H/(thiophen-2-yl) SO₂Me CH₂CO₂H CH₂ 2,4-Cl₂-pheH/(thiophen-2-yl) SO₂Me CH₂CO₂H CH₂ 3,4-Cl₂-phe H/(thiophen-2-yl) FCH₂CO₂H CH₂ 2,4-Cl₂-phe H/(thiophen-2-yl) F CH₂CO₂H CH₂ 3,4-Cl₂-pheH/(thiophen-2-yl) F CH₂CO₂H CH₂ 4-Cl-phe H/(2-oxazolyl) F CH₂CO₂H CH₂2,4-Cl₂-phe H/(2-oxazolyl) F CH₂CO₂H CH₂ 3,4-Cl₂-phe H/(2-oxazolyl) FCH₂CO₂H CH₂ 4-Cl-phe H/(2-oxazolyl) SO₂Me CH₂CO₂H CH₂ 2,4-Cl₂-pheH/(2-oxazolyl) SO₂Me CH₂CO₂H CH₂ 3,4-Cl₂-phe H/(2-oxazolyl) SO₂MeCH₂CO₂H CH₂ 4-Cl-phe H/i-Pr SO₂Me CH₂CO₂H CH₂ 2,4-Cl₂-phe H/i-Pr SO₂MeCH₂CO₂H CH₂ 3,4-Cl₂-phe H/i-Pr SO₂Me CH₂CO₂H CH₂ 4-Cl-phe H/c-Pr SO₂MeCH₂CO₂H CH₂ 2,4-Cl₂-phe H/c-Pr SO₂Me CH₂CO₂H CH₂ 3,4-Cl₂-phe H/c-PrSO₂Me CH₂CO₂H CH₂ 4-Cl-phe H/i-Pr F CH₂CO₂H CH₂ 2,4-Cl₂-phe H/i-Pr FCH₂CO₂H CH₂ 3,4-Cl₂-phe H/i-Pr F CH₂CO₂H CH₂ 4-Cl-phe H/c-Pr F CH₂CO₂HCH₂ 2,4-Cl₂-phe H/c-Pr F CH₂CO₂H CH₂ 3,4-Cl₂-phe H/c-Pr F CH₂CO₂H CH₂4-Cl-phe H/i-Bu F CH₂CO₂H CH₂ 2,4-Cl₂-phe H/i-Bu F CH₂CO₂H CH₂3,4-Cl₂-phe H/i-Bu F CH₂CO₂H CH₂ 4-Cl-phe H/Br F CH₂CO₂H CH₂ 2,4-Cl₂-pheH/Br F CH₂CO₂H CH₂ 3,4-Cl₂-phe H/Br F CH₂CO₂H CH₂ 4-Cl-phe H/I F CH₂CO₂HCH₂ 2,4-Cl₂-phe H/I F CH₂CO₂H CH₂ 3,4-Cl₂-phe H/I F CH₂CO₂H CH₂ 4-Cl-pheH/Cl F CH₂CO₂H CH₂ 2,4-Cl₂-phe H/Cl F CH₂CO₂H CH₂ 3,4-Cl₂-phe H/Cl FCH₂CO₂H CH₂ 4-Cl-phe H/F c-Bu CH₂CO₂H CH₂ 2,4-Cl₂-phe H/F c-Bu CH₂CO₂HCH₂ 3,4-Cl₂-phe H/F c-Bu CH₂CO₂H CH₂ 4-Cl-phe H/F C(OR)(CH₂)₃ CH₂CO₂HCH₂ 2,4-Cl₂-phe H/F C(OR)(CH₂)₃ CH₂CO₂H CH₂ 3,4-Cl₂-phe H/F C(OR)(CH₂)₃CH₂CO₂H CH₂ 4-Cl-phe H/SO₂Me C(OH)(CH2)3 CH₂CO₂H CH₂ 2,4-Cl₂-phe H/SO₂MeC(OH)(CH2)3 CH₂CO₂H CH₂ 3,4-Cl₂-phe H/SO₂Me C(OH)(CH2)3 CH₂CO₂H CH₂4-Cl-phe H/SO₂Me (2-oxetanyl) CH₂CO₂H CH₂ 2,4-Cl₂-phe H/SO₂Me(2-oxetanyl) CH₂CO₂H CH₂ 3,4-Cl₂-phe H/SO₂Me (2-oxetanyl) CH₂CO₂H CH₂4-Cl-phe H/F (2-oxetanyl) CH₂CO₂H CH₂ 2,4-Cl₂-phe H/F (2-oxetanyl)CH₂CO₂H CH₂ 3,4-Cl₂-phe H/F (2-oxetanyl) CH₂CO₂H CH₂ 4-Cl-phe

[0169] TABLE IV

R¹/R² R³ A—Q/R⁶ Y¹ Ar H/SO₂Me C(O)CH₃ CH₂CO₂H S 4-Cl-phe H/SO₂MeCH(OH)CH₃ CH₂CO₂H O 4-Cl-phe H/SO₂Me Br CH₂CO₂H CH₂ 2,4-Cl₂-phe H/SO₂MeCHCH₂ CH₂CO₂H CH₂ 4-Cl-phe H/SO₂Me c-pr CH₂CO₂H O 4-Cl-phe H/SO₂Me(thiophen-2-yl) CH₂CO₂H CH₂ 4-Cl-phe H/SO₂NMe₂ H CH₂CO₂H S 4-Cl-phe H/FBr CH₂CO₂H/CH₃ CH₂ 4-Cl-phe H/Br C(O)CH₃ CH₂CO₂H NH 4-Cl-phe H/CN HCH₂CO₂H S 2,4-Cl₂-phe H/CN H CH₂CO₂H S 3,4-Cl₂-phe H/CN H CH₂CO₂H S4-Cl-phe H/F H CH₂CO₂H CO 2,4-Cl₂-phe H/F H CH₂CO₂H CO 3,4-Cl₂-phe H/F HCH₂CO₂H CO 4-Cl-phe H/CF₃ H CH₂CO₂H CH₂ 2,4-Cl₂-phe H/CF₃ H CH₂CO₂H CH₂3,4-Cl₂-phe H/CF₃ H CH₂CO₂H CHCH₃ 3,4-Cl₂-phe H/CF₃ H CH₂CO₂H CH₂4-Cl-phe H/F H CH(CH₃)CO₂H CH₂ 2,4-Cl₂-phe H/F H CH₂CO₂H CH₂ 2,4-Cl₂-pheH/F H CH₂CO₂H CH₂ 3,4-Cl₂-phe H/F H CH₂CO₂H CH₂ 4-Cl-phe H/F H CH₂CO₂H O2-Cl-4-F-phe H/F H CH₂CO₂H CH₂ 2-F-4-Cl-phe H/F H CH₂CO₂H 1,1-cPr4-Cl-phe H/F H CH₂CO₂H CH₂ 2,4,6-Cl₃-phe H/F H CH₂CO₂H CH₂ 2,3,4-Cl₃-pheH/H F CH₂CO₂H S 2-Cl-4-CN-phe H/F H CH₂CO₂H CH₂ 2-Cl-4-COCH₃-phe H/F HCH₂CO₂H CH₂ 4-CN-phe H/F H CH₂CO₂H CH₂ 4-COCH₃-phe H/F H CH₂CO₂H CH₂3-Cl-4-CN-phe H/F H CH₂CO₂H CH₂ 3-Cl-4-COCH₃-phe H/F H CH₂CO₂H CH₂4-CF₃-phe H/F H CH₂CO₂H CH₂ 2-Cl-4-CF₃-phe H/F H CH₂CO₂H CH₂3-Cl-4-CF₃-phe H/F H CH₂CO₂H CH₂ 2,6-Cl₂-phe H/F H CH₂CO₂H CH₂2,4,6-F₃-phe H/F CO₂Me CH(CH₃)CO₂H CH₂ 2,4-Cl₂-phe H/F CO₂Me CH₂CO₂H CH₂2,4-Cl₂-phe H/F CO₂Me CH₂CO₂H NMe 3,4-Cl₂-phe H/F CO₂Me CH₂CO₂H CH₂4-Cl-phe H/F CO₂Me CH₂CO₂H CH₂ 2-Cl-4-F-phe H/F CO₂Me CH₂CO₂H CH₂2-F-4-Cl-phe H/F CO₂Me CH₂CO₂H 1,1-c-pr 4-Cl-phe H/F CO₂Me CH₂CO₂H CH₂2,4,6-Cl₃-phe H/F CO₂Me CH₂CO₂H CH₂ 2,3,4-Cl₃-phe H/F CO₂Me CH₂CO₂H CH₂2-Br-4-Cl-phe H/F CO₂Me CO₂Me CH₂ 2-Cl-4-Br-phe H/F CO₂Me CO₂Me CH₂2-F-4-Br-phe H/F CO₂Me CO₂Me CH₂ 2-Cl-4-CN-phe H/F CO₂Me CO₂Me CH₂2-Cl-4-COCH₃-phe H/F CO₂Me CO₂Me CH₂ 4-CN-phe H/F CO₂Me CO₂Me CH₂4-COCH₃-phe H/F CO₂Me CO₂Me CH₂ 3-Cl-4-CN-phe H/F CO₂Me CO₂Me CH₂3-Cl-4-COCH₃-phe H/F CO₂Me CO₂Me CH₂ 4-CF₃-phe H/F CO₂Me CH₂CO₂H CH₂2-Cl-4-CF₃-phe H/F CO₂Me CH₂CO₂H CH₂ 3-Cl-4-CF₃-phe H/F CO₂Me CH₂CO₂HCH₂ 2,6-Cl₂-phe H/F CO₂Me CH₂CO₂H CH₂ 2,4,6-F₃-phe H/F SOMe CH(CH₃)CO₂HCH₂ 2,4-Cl₂-phe H/F SOMe CH₂CO₂H CH₂ 2,4-Cl₂-phe H/F SOMe CH₂CO₂H CH₂3,4-Cl₂-phe H/F SOMe CH₂CO₂H CH₂ 2 4-Cl-phe H/F SOMe CH₂CO₂H CH₂2-Cl-4-F-phe H/F SOMe CH₂CO₂H CH₂ 2-F-4-Cl-phe H/F SOMe CH₂CO₂H 1,1-c-pr4-Cl-phe H/F SOMe CH₂CO₂H CH₂ 2,4,6-Cl₃-phe H/F SOMe CH₂CO₂H CH₂2,3,4-Cl₃-phe H/F SOMe CH₂CO₂H CH₂ 2-Br-4-Cl-phe H/F SOMe CH₂CO₂H CH₂2-C1-4-Br-phe H/F SOMe CH₂CO₂H CH₂ 2-F-4-Br-phe H/F SOMe CH₂CO₂H CH₂2-Cl-4-CN-phe H/F SOMe CH₂CO₂H CH₂ 2-Cl-4-COCH₃-phe F/F SOMe CH₂CO₂H CH₂4-CN-phe H/F SOMe CH₂CO₂H CH₂ 4-COCH₃-phe H/F SOMe CH₂CO₂H S3-Cl-4-CN-phe H/F SOMe CH₂CO₂H CH₂ 3-Cl-4-COCH₃-phe H/F SOMe CH₂CO₂H CH₂4-CF₃-phe H/F SOMe CH₂CO₂H CH₂ 2-Cl-4-CF₃-phe H/F SOMe CH₂CO₂H CH₂3-Cl-4-CF₃-phe H/F SOMe CH₂CO₂H CH₂ 2,6-Cl₂-phe H/F SOMe CH₂CO₂H CH₂2,4,6-F₃-phe H/SO₂Me. C(O)CH₃ CH₂CO₂H CH₂ 2,4-Cl₂-phe H/SO₂Me C(O)CH₃CH₂CO₂H CH₂ 3,4-Cl₂-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 2-Cl-4-F-phe H/SO₂MeC(O)CH₃ CH₂CO₂H CH₂ 2-F-4-Cl-phe H/SO₂Me C(O)CH₃ CH₂CO₂H 1,1-c-pr4-Cl-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 2,4,6-Cl₃-phe H/SO₂Me C(O)CH₃CH₂CO₂H CH₂ 2,3,4-Cl₃-phe SO₂Me/H C(O)CH₃ CH₂CO₂H CH₂ 2-Br-4-Cl-pheH/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 2-Cl-4-Br-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂2-F-4-Br-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 2-Cl-4-CN-phe H/SO₂Me C(O)CH₃CH₂CO₂H CH₂ 2-Cl-4-COCH₃-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 4-CN-pheH/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 4-COCH₃-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂3-Cl-4-CN-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 3-Cl-4-COCH₃-phe H/SO₂MeC(O)CH₃ CH₂CO₂H CH₂ 4-CF₃-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 2-Cl-4-CF₃-pheH/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 3-Cl-4-CF₃-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂2,6-Cl₂-phe H/SO₂Me C(O)CH₃ CH₂CO₂H CH₂ 2,4,6-F₃-phe H/SO₂Me CH(OH)CH₃CH(CH₃)CO₂H CH₂ 2,4-Cl₂-phe H/SO₂Me CH(OH)CH₃ CH₂CO₂H CH₂ 2,4-Cl₂-pheH/SO₂Me CH(OH)CH₃ CH₂CO₂H CH₂ 3,4-Cl₂-phe H/SO₂Me CH(OH)CH₃ CH₂CO₂H CH₂2-Cl-4-F-phe H/SO₂Me CH(OH)CH₃ CH₂CO₂H CH₂ 2-F-4-Cl-phe H/SO₂MeCH(OH)CH₃ CH₂CO₂H 1,1-c-pr 4-Cl-phe H/SO₂Me CH(OH)CH₃ CH₂CO₂H CH₂2,4,6-Cl₃-phe H/SO₂Me CH(OH)CH₃ CH₂CO₂H CH₂ 2,3,4-Cl₃-phe H/SO₂MeCH(OH)CH₃ CH₂CO₂H CH₂ 2-Br-4-Cl-phe H/CH(OH)CH₃ SO₂Me CH₂CO₂H CH₂2-Cl-4-Br-phe H/CH(OH)CH₃ SO₂Me CH₂CO₂H CH₂ 2-F-4-Br-phe H/CH(OH)CH₃SO₂Me CH₂CO₂H CH₂ 2-Cl-4-CN-phe H/CH(OH)CH₃ SO₂Me CH₂CO₂H CH₂2-Cl-4-COCH₃-phe H/CH(OH)CH₃ SO₂Me CH₂CO₂H CH₂ 4-CN-phe H/CH(OH)CH₃SO₂Me CH₂CO₂H CH₂ 4-COCH₃-phe H/SO₂Me CH(OH)CH₃ CH₂CO₂H CH₂3-Cl-4-CN-phe H/SO₂Me CH(OH)CH₃ CH₂CO₂H CH₂ 3-Cl-4-COCH₃-phe H/SO₂MeCH(OH)CH₃ CH₂CO₂H CH₂ 4-CF₃-phe H/SO₂Me CH(OH)CH₃ CH₂CO₂H CH₂2-Cl-4-CF₃-phe H/SO₂Me CH(OH)CH₃ CH₂CO₂H CH₂ 3-Cl-4-CF₃-phe H/SO₂MeCH(OH)CH₃ CH₂CO₂H CH₂ 2,6-Cl₂-phe H/CH(OH)CH₃ SO₂Me CH₂CO₂H CH₂2,4,6-F₃-phe H/CO₂CH₃ SO₂Me CH(CH₃)CO₂R CH₂ 2,4-Cl₂2-phe H/CO₂CH₃ SO₂MeCH₂CO₂H CH₂ 2,4-Cl₂2-Phe H/SO₂Me CO₂CH₃ CH₂CO₂H CH₂ 3,4-Cl₂-phe H/SO₂MeCO₂CH₃ CH₂CO₂H CH₂ 4-Cl-phe H/SO₂Me CO₂CH₃ CH₂CO₂H CH₂ 2-Cl-4-F-pheH/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2-F-4-Cl-phe H/CO₂CH₃ SO₂Me CH₂CO₂H 1,1-c-pr4-Cl-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2,4,6-Cl₃-phe H/CO₂CH₃ SO₂Me CH₂CO₂HCH₂ 2,3,4-Cl₃-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2-Br-4-Cl-phe H/CO₂CH₃SO₂Me CH₂CO₂H CH₂ 2-Cl-4-Br-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2-F-4-Br-pheH/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2-Cl-4-CN-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂2-Cl-4-COCH₃-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 4-CN-phe H/CO₂CH₃ SO₂MeCH₂CO₂H CH₂ 4-COCH₃-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 3-Cl-4-CN-pheH/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 3-Cl-4-COCH₃-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂4-CF₃-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2-Cl-4-CF₃-phe H/CO₂CH₃ SO₂MeCH₂CO₂H CH₂ 3-Cl-4-CF₃-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2,6-Cl₂-pheH/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2,4,6-F₃-phe H/CO₂CH₃ SO₂Me CH₂CO₂H SO₂2,4-Cl₂-phe H/CO₂CH₃ SO₂Me CH₂CO₂H SO₂ 3,4-Cl₂-phe H/CO₂CH₃ SO₂MeCH₂CO₂H SO₂ 4-Cl-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 2,4-Cl₂-phe H/CO₂CH₃SO₂Me CH₂CO₂H CH₂ 3,4-Cl₂-phe H/CO₂CH₃ SO₂Me CH₂CO₂H CH₂ 4-Cl-pheH/CO₂CH₃ SO₂Me CHCH₃CO₂H CH₂ 2,4-Cl₂-phe H/CO₂CH₃ SO₂Me CHCH₃CO₂H CH₂3,4-Cl₂-phe H/CO₂CH₃ SO₂Me CHCH₃CO₂H CH₂ 4-Cl-phe H/CO₂CH₃ SO₂MeCH₂CO₂H/CH₃ CH₂ 2,4-Cl₂-phe H/CO₂CH₃ SO₂Me CH₂CO₂H/CH₃ CH₂ 3,4-Cl₂-pheH/CO₂CH₃ SO₂Me CH₂CO₂H/CH₃ CH₂ 4-Cl-phe H/SO₂Me 4-CO₂CH₂CH₃ CH₂CO₂H CH₂3,4-Cl₂-phe H/SO₂Me 4-CO₂CH₂CH₃ CH₂CO₂H CH₂ 4-Cl-phe H/C(OH)(CH₂)₂ SO₂MeCH₂CO₂H CH₂ 2,4-Cl₂-phe H/C(OH)(CH₂)₂ SO₂Me CH₂CO₂H CH₂ 3,4-Cl₂-pheH/C(OH)(CH₂)₂ SO₂Me CH₂CO₂H CH₂ 4-Cl-phe H/(thiophen-2-yl) SO₂Me CH₂CO₂HCH₂ 2,4-Cl₂-phe H/(thiophen-2-yl) SO₂Me CH₂CO₂H CH₂ 3,4-Cl₂-pheH/(thiophen-2-yl) F CH₂CO₂H CH₂ 2,4-Cl₂-phe H/(thiophen-2-yl F CH₂CO₂HCH₂ 3,4-Cl₂-phe H/(tbiophen-2-yl) F CH₂CO₂H CH₂ 4-Cl-phe H/(2-oxazolyl)F CH₂CO₂H CH₂ 2,4-Cl₂-phe H/(2-oxazolyl) F CH₂CO₂H CH₂ 3,4-Cl₂-pheH/(2-oxazolyl) F CH₂CO₂H CH₂ 4-Cl-phe H/(2-oxazolyl) SO₂Me CH₂CO₂H CH₂2,4-Cl₂-phe H/(2-oxazolyl) SO₂Me CH₂CO₂H CH₂ 3,4-Cl₂-phe H/(2-oxazolyl)SO₂Me CH₂CO₂H CH₂ 4-Cl-phe H/i-Pr SO₂Me CH₂CO₂H CH₂ 2,4-Cl₂-phe H/i-PrSO₂Me CH₂CO₂H CH₂ 3,4-Cl₂-phe H/i-Pr SO₂Me CH₂CO₂H CH₂ 4-Cl-phe H/c-PrSO₂Me CH₂CO₂H CH₂ 2,4-Cl₂-phe H/c-Pr SO₂Me CH₂CO₂H CH₂ 3,4-Cl₂-pheH/c-Pr SO₂Me CH₂CO₂H CH₂ 4-Cl-phe H/i-Pr F CH₂CO₂H CH₂ 2,4-Cl₂-pheH/i-Pr F CH₂CO₂H CH₂ 3,4-Cl₂-phe H/i-Pr F CH₂CO₂H CH₂ 4-Cl-phe H/c-Pr FCH₂CO₂H CH₂ 2,4-Cl₂-phe H/c-Pr F CH₂CO₂H CH₂ 3,4-Cl₂-phe H/c-Pr FCH₂CO₂H CH₂ 4-Cl-phe H/i-Bu F CH₂CO₂H CH₂ 2,4-Cl₂-phe H/i-Bu F CH₂CO₂HCH₂ 3,4-Cl₂-phe H/i-Bu F CH₂CO₂H CH₂ 4-Cl-phe H/Br F CH₂CO₂H CH₂2,4-Cl₂-phe H/Br F CH₂CO₂H CH₂ 3,4-Cl₂-phe H/Br F CH₂CO₂H CH₂ 4-Cl-pheH/I F CH₂CO₂H CH₂ 2,4-Cl₂-phe H/I F CH₂CO₂H CH₂ 3,4-Cl₂-phe H/I FCH₂CO₂H CH₂ 4-Cl-phe H/Cl F CH₂CO₂H CH₂ 2,4-Cl₂-phe H/Cl F CH₂CO₂H CH₂3,4-Cl₂-phe H/Cl F CH₂CO₂H CH₂ 4-Cl-phe H/F c-Bu CH₂CO₂H CH₂ 2,4-Cl₂-pheH/F c-Bu CH₂CO₂H CH₂ 3,4-Cl₂-phe H/F c-Bu CH₂CO₂H CH₂ 4-Cl-phe H/FC(OH)(CH₂)₃ CH₂CO₂H CH₂ 2,4-Cl₂-phe H/F C(OH)(CH₂)₃ CH₂CO₂H CH₂3,4-Cl₂-phe H/P C(OH)(CH₂)₃ CH₂CO₂H CH₂ 4-Cl-phe H/SO₂Me C(OH)(CH₂)₃CH₂CO₂H CH₂ 2,4-Cl₂-phe H/SO₂Me C(OH)(CH₂)₃ CH₂CO₂H CH₂ 3,4-Cl₂-pheH/SO₂Me C(OH)(CH₂)₃ CH₂CO₂H CH₂ 4-Cl-phe H/SO₂Me (2-oxetanyl) CH₂CO₂HCH₂ 2,4-Cl₂-phe H/SO₂Me (2-oxetanyl) CH₂CO₂H CH₂ 3,4-Cl₂-phe H/SO₂Me(2-oxetanyl) CH₂CO₂H CH₂ 4-Cl-phe H/F (2-oxetanyl) CH₂CO₂H CH₂2,4-Cl₂-phe H/F (2-oxetanyl) CH₂CO₂H CH₂ 3,4-Cl₂-phe H/F (2-oxetanyl)CH₂CO₂H CH₂ 4-Cl-phe

[0170] TABLE V

R¹ R² n A-Q Y1 Ar F H 1 CH₂CO₂H O 2-Br-4-Cl-phe F H 1 CH₂CO₂H O2-Cl-4-Br-phe F H 1 CH₂CO₂H CH 2-F-4-Br-phe C(O)CH₃ SO₂Me 1 CH(CH₃)CO₂HCH₂ 2,4-Cl₂-phe 5-F H 2 CH₂CO₂H CH₂ 2-Br-4-Cl-phe 5-F H 2 CH₂CO₂H O2-Cl-4-Br-phe 5-F H 2 CH₂CO₂H S 2-F-4-Br-phe C(O)CH₃ SO₂Me 2 CH(CH₃)CO₂HCH₂ 2,4-Cl₂-phe

[0171] Assays for Determining Biological Activity

[0172] Compounds of formula I can be tested using the following assaysto determine their prostanoid antagonist or agonist activity in vitroand in vivo and their selectivity. The prostaglandin receptor activitiesdemonstrated are DP, EP₁, EP₂, EP₃, EP₄, FP, IP and TP.

[0173] Stable Expression of Prostanoid Receptors in the Human EmbryonicKidney (HEK) 293(EBNA) Cell Line

[0174] Prostanoid receptor cDNAs corresponding to full length codingsequences are subcloned into the appropriate sites of mammalianexpression vectors and transfected into HEK 293(ebna) cells. HEK293(ebna) cells expressing the individual cDNAs are grown underselection and individual colonies are isolated after 2-3 weeks of growthusing the cloning ring method and subsequently expanded into clonal celllines.

[0175] Prostanoid Receptor Binding Assays

[0176] HEK 293(ebna) cells are maintained in culture, harvested andmembranes are prepared by differential centrifugation, following lysisof the cells in the presence of protease inhibitors, for use in receptorbinding assays. Prostanoid receptor binding assays are performed in 10mM MES/KOH (pH 6.0) (EPs, FP and TP) or 10 mM HEPES/KOH (pH 7.4) (DP andIP), containing 1 mM EDTA, 10 mM divalent cation and the appropriateradioligand. The reaction is initiated by addition of membrane protein.Ligands are added in dimethylsulfoxide which is kept constant at 1%(v/v) in all incubations. Non-specific binding is determined in thepresence of 1 μM of the corresponding non-radioactive prostanoid.Incubations are conducted for 60 min at room temperature or 30° C. andterminated by rapid filtration. Specific binding is calculated bysubtracting non specific binding from total binding. The residualspecific binding at each ligand concentration is calculated andexpressed as a function of ligand concentration in order to constructsiginoidal concentration-response curves for determination of ligandaffinity.

[0177] Prostanoid Receptor Agonist and Antagonist Assays

[0178] Whole cell second messenger assays measuring stimulation (EP₂,EP₄, DP and IP in HEK 293(ebna) cells) or inhibition (EP₃ in humanerythroleukemia (HEL) cells) of intracellular cAMP accumulation ormobilization of intracellular calcium (EP₁, FP and TP in HEK 293(ebna)cells stably transfected with apo-aequorin) are performed to determinewhether receptor ligands are agonists or antagonists. For cAMP assays,cells are harvested and resuspended in HBSS containing 25 mM HEPES, pH7.4. Incubations contain 100 μM RO-20174 (phosphodiesterase type IVinhibitor, available from Biomol) and, in the case of the EP₃ inhibitionassay only, 15 μM forskolin to stimulate cAMP production. Samples areincubated at 37° C. for 10 min, the reaction is terminated and cAMPlevels are then measured. For calcium mobilization assays, cells arecharged with the co-factors reduced glutathione and coelenterazine,harvested and resuspended in Ham's F12 medium. Calcium mobilization ismeasured by monitoring luminescence provoked by calcium binding to theintracellular photoprotein aequorin. Ligands are added indimethylsulfoxide which is kept constant at 1% (v/v) in all incubations.For agonists, second messenger responses are expressed as a function ofligand concentration and both EC₅₀ values and the maximum response ascompared to a prostanoid standard are calculated. For antagonists, theability of a ligand to inhibit an agonist response is determined bySchild analysis and both K_(B) and slope values are calculated.

[0179] Prevention of PGD2 or Allergen Induced Nasal Congestion inAllergic Sheep

[0180] Animal preparation: Healthy adult sheeps (18-50 kg) are used.These animals are selected on the basis of a natural positive skinreaction to an intradermal injection of Ascaris suum extract.

[0181] Measurements of nasal congestion: The experiment is performed onconscious animals. They are restained in a cart in a prone position withtheir heads immobilized. Nasal airway resistance (NAR) is measured usinga modified mask rhinometry technique. A topical anaesthesia (2%lidocaine) is applied to the nasal passage for the insertion of anasotracheal tube. The maximal end of the tube is connected to apneumaotachograph and a flow and pressure signal is recorded on anoscilloscope linked to a computer for on-line calculation of NAR. Nasalprovocation is performed by the administration of an aerosolizedsolution (10 puffs/nostril). Changes in the NAR congestion are recordedprior to and for 60-120 minutes post-challenge.

[0182] Prevention of PGD2 and Allergen Induced Nasal Obstruction inCynomolgus Monkey

[0183] Animal preparation: Healthy adult male cynomologus monkeys (4-10kg) are used. These animals are selected on the basis of a naturalpositive skin reaction to an intradermal injection of Ascaris suumextract. Before each experiment, the monkey selected for a study isfasted overnight with water provided at libitum. The next morning, theanimal is sedated with ketamine (10-15 mg/kg i.m.) before being removedfrom its home cage. It is placed on a heated table (36° C.) and injectedwith a bolus dose (5-12 mg/kg i.v.) of propofol. The animal is intubatedwith a cuffed endotracheal tube (4-6 mm I.D.) and anaesthesia ismaintained via a continuous intravenous infusion of propofol (25-30mg/kg/h). Vital signs (heart rate, blood pressure, respiratory rate,body temperature) are monitored throughout the experiment.

[0184] Measurements of nasal congestion: A measurement of the animalrespiratory resistance is taken via a pneumotachograph connected to theendotracheal tube to ensure that it is normal. An Ecovision accousticrhinometer is used to evaluate nasal congestion. This technique gives anon-invasive 2D echogram of the inside of the nose. The nasal volume andthe minimal cross-sectional area along the length of the nasal cavityare computed within 10 seconds by a laptop computer equipped with acustom software (Hood Laboratories, Mass, U.S.A.). Nasal challenge isdelivered directly to the animal's nasal cavity (50 μL volume). Thechanges in nasal congestion are recorded prior to and for 60-120 minutespost-challenge. If nasal congestion occurs, it will translate into areduction in the nasal volume.

[0185] Pulmonary Mechanics in Trained Conscious Squirrel Monkeys

[0186] The test procedure involves placing trained squirrel monkeys inchairs in aerosol exposure chambers. For control purposes, pulmonarymechanics measurements of respiratory parameters are recorded for aperiod of about 30 minutes to establish each monkey's normal controlvalues for that day. For oral administration, compounds are dissolved orsuspended in a 1% methocel solution (methylcellulose, 65HG, 400 cps) andgiven in a volume of 1 mL/kg body weight. For aerosol administration ofcompounds, a DeVilbiss ultrasonic nebulizer is utilized. Pretreatmentperiods vary from 5 minutes to 4 hours before the monkeys are challengedwith aerosol doses of either PGD2 or Ascaris suum antigen; 1:25dilution.

[0187] Following challenge, each minute of data is calculated bycomputer as a percent change from control values for each respiratoryparameter including airway resistance (R_(L)) and dynamic compliance(C_(dyn)). The results for each test compound are subsequently obtainedfor a minimum period of 60 minutes post-challenge which are thencompared to previously obtained historical baseline control values forthat monkey. In addition, the overall values for 60 minutespost-challenge for each monkey (historical baseline values and testvalues) are averaged separately and are used to calculate the overallpercent inhibition of mediator or Ascaris antigen response by the testcompound. For statistical analysis, paired t-test is used. (References:McFarlane, C. S. et al., Prostaglandins, 28, 173-182 (1984) andMcFarlane, C. S. et al., Agents Actions, 22, 63-68 (1987).)

[0188] Prevention of Induced Bronchoconstriction in Allergic Sheep

[0189] Animal Preparation: Adult sheep with a mean weight of 35 kg(range, 18 to 50 kg) are used. All animals used meet two criteria: a)they have a natural cutaneous reaction to 1:1,000 or 1:10,000 dilutionsof Ascaris suum extract (Greer Diagnostics, Lenois, N.C.); and b) theyhave previously responded to inhalation challenge with Ascaris suum withboth an acute bronchoconstriction and a late bronchial obstruction (W.M. Abraham et al., Am. Rev. Resp. Dis., 128, 839-44 (1983)).

[0190] Measurement of Airway Mechanics: The unsedated sheep arerestrained in a cart in the prone position with their heads immobilized.After topical anesthesia of the nasal passages with 2% lidocainesolution, a balloon catheter is advanced through one nostril into thelower esophagus. The animals are then intubated with a cuffedendotracheal tube through the other nostril using a flexible fiberopticbronchoscope as a guide. Pleural pressure is estimated with theesophageal balloon catheter (filled with one mL of air), which ispositioned such that inspiration produces a negative pressure deflectionwith clearly discernible cardiogenic oscillations. Lateral pressure inthe trachea is measured with a sidehole catheter (inner dimension, 2.5mm) advanced through and positioned distal to the tip of thenasotracheal tube. Transpulmonary pressure, the difference betweentracheal pressure and pleural pressure, is measured with a differentialpressure transducer (DP45; Validyne Corp., Northridge, Calif.). For themeasurement of pulmonary resistance (R_(L)), the maximal end of thenasotrachel tube is connected to a pneumotachograph (Fleisch, DynaSciences, Blue Bell, Pa.). The signals of flow and transpulmonarypressure are recorded on an oscilloscope (Model DR-12; Electronics forMedicine, White Plains, N.Y.) which is linked to a PDP-11 Digitalcomputer (Digital Equipment Corp., Maynard, Mass.) for on-linecalculation of R_(L) from transpulnonary pressure, respiratory volumeobtained by integration and flow. Analysis of 10-15 breaths is used forthe determination of R_(L). Thoracic gas volume (V_(tg)) is measured ina body plethysmograph, to obtain specific pulmonary resistance(SR_(L)=R_(L)·V_(tg)).

[0191] The invention will now be illustrated in the followingnon-limiting Examples in which, unless otherwise stated:

[0192] 1. All the end products of the formula I were analyzed by NMR,TLC and elementary analysis or mass spectroscopy.

[0193] 2. Intermediates were analyzed by NMR and TLC.

[0194] 3. Most compounds were purified by flash chromatography on silicagel, recrystallization and/or swish (suspension in a solvent followed byfiltration of the solid).

[0195] 4. The course of reactions was followed by thin layerchromatography (TLC) and reaction times are given for illustration only.

[0196] 5. The enantiomeric excess was measured on normal phase HPLC witha chiral column: ChiralPak AD; 250×4.6 mm.

EXAMPLE 1

[0197](+/−)-[10-(4-Chlorobenzyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]aceticacid

[0198] STEP 1: 3-(4-Chlorobenzyl)-1H-indole

[0199] To a vigorously stirred solution of 30 mL of 3M MeMgBr in etherwas added dropwise a solution of 10 g of indole in 100 mL of ether.After addition was finished, the mixture was heated to reflux for 30minutes and treated with 22 g of p-chlorobenzyl bromide. The reactionmixture was refluxed for 3 hours, quenched with 50 mL of saturatedaqueous solution of NH₄Cl, and extracted with 200 mL of ether. The etherlayer was dried over Na₂SO₄ and concentrated. The residue was purifiedby silica gel flash chromatography eluted with toluene to give 6 g ofthe title compound as a beige solid.

[0200]¹H NMR (acetone-d₆) δ 7.42 (1H, d), 7.38 (1H, d), 7.26 (4H, dd),7.15 (1H, s), 7.07 (1H, t), 6.95 (1H, t), 4.10 (2H, s).

[0201] STEP 2: 2-Bromo-3-(4-chlorobenzyl)-1H-indole

[0202] To a solution of 2 g of 3-(4-chlorobenzyl)-1H-indole in 50 mL ofCCl₄ was added 1.8 g of NBS. The reaction mixture was stirred for 1 hourat room temperature and diluted with 50 mL of 5:1 hexane/EtOAc. Themixture was then filtered through a pad of silica gel and the filtratewas concentrated under reduced pressure to give the crude titlecompound, which was used for the next step without further purification.

[0203]¹H NMR (acetone-d₆) δ 7.40 (1H, d), 7.35 (1H, d), 7.25 (4H, dd),7.10 (1H, t), 6.09 (1H, t), 4.08 (2H, s)

[0204] STEP 3: Ethyl4-[2-bromo-3-(4-chlorobenzyl)-1H-1-indolyl]butanoate

[0205] To a vigorously stirred solution of 0.32 g of the product fromStep 2 in 5 mL of DMF was added sequentially 0.045 g NaH (60% in mineraloil), 0.2 mL of ethyl 4-bromobutyrate and 0.02 g of n-Bu₄NI. The mixturewas stirred for 45 minutes at room temperature, quenched with 5 mL ofsaturated aqueous solution of NH₄Cl and 5 mL of water, and extractedwith 40 mL of 1:1 hexane/EtOAc. The extract was dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel flashchromatography eluted with 9:1 hexane/EtOAc to give 0.3 g of the titlecompound as an oil.

[0206]¹H NMR (acetone-d₆) δ 7.49 (1H, d), 7.42 (1H, d), 7.27 (4H, dd),7.16 (1H, t), 7.02 (1H, t), 4.35 (2H, t), 4.10 (2H, s), 4.05 (2H, q),2.38 (2H, t), 2.12 (2H, m), 1.18 (3H, t).

[0207] STEP 4: 4-[2-Bromo-3-(4-chlorobenzyl)-1H-1-indolyl]butanal

[0208] To a vigorously stirred solution of 0.3 g of the product fromStep 3 in 5 mL of THF cooled at −78° C. was added dropwise a solution ofdiisobutylaluminum hydride (4 mL, 1 M in hexane). After stirring for 30minutes at −78° C., the reaction was quenched with 1 mL of acetonefollowed by 10 mL of 20% aqueous solution of potassium sodium tartrate.The mixture was extracted with 20 mL of 1:1 hexane/EtOAc and the extractwas dried over Na₂SO₄ and concentrated. The residue was purified bysilica gel flash chromatography eluted with 8:1 hexane/EtOAc to give0.19 g of the title compound as an oil.

[0209]¹H NMR (acetone-d₆) δ 9.72 (1H, s), 7.50 (1H, d), 7.42 (1H, d),7.27 (4H, dd), 7.16 (1H, t), 7.01 (1H, t), 4.32 (2H, t), 4.10 (2H, s),2.56 (2H, t), 2.06 (2H, m).

[0210] STEP 5: Ethyl(E)-6-[2-bromo-3-(4-chlorobenzyl)-1H-1-indolyl]-2-hexenoate

[0211] To a solution of the product obtained in Step 4 in 8 mL of THFwas added 0.3 g (carbethoxymethylene)triphenylphosphorane. The reactionmixture was stirred for 2 hours at 50° C. and diluted with 20 mL of 10:1hexane/EtOAc. The mixture was then filtered through a pad of silica geland the filtrate was concentrated under reduced pressure. The residuewas purified by silica gel flash chromatography eluted with 9:1hexane/EtOAc to give 0.2 g of the title compound as an oil.

[0212] STEP 6: E/Z-Ethyl2-[10-(4-chlorobenzyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yliden]acetate

[0213] To a vigorously stirred solution of 0.13 g of the product fromStep 5 in 4 mL of DMF under N₂ atmosphere was added sequentially 0.75 gof n-Bu₄NCI, 0.1 mL of Et₃N and 0.022 g of Pd(AcO)₂. The mixture wasstirred for 1 hour at 75° C. and then concentrated under reducedpressure. The residue was purified by silica gel flash chromatographyeluted with 6:1 hexane/EtOAc to give 0.07 g of the more mobile isomerfollowed by 0.06 g of the less mobile isomer.

[0214]¹H NMR (acetone-d₆) (more mobile isomer) δ 7.56 (1H, d), 7.43 (1H,d), 7.30 (2H, d), 7.23 (1H, t), 7.18 (2H, d), 7.19 (1H, t), 6.08 (1H,s), 4.35 (2H, s), 4.23 (2H, t), 4.10 (2H, q), 3.28 (2H, m), 2.14 (2H,m), 1.20 (3H, t).

[0215]¹H NMR (acetone-d₆) (less mobile isomer) δ 7.38 (1H, d), 7.34 (1H,d), 7.22 (2H, d), 7.10-7.20 (3H, m), 7.45(2H, t), 7.45 (1H, t), 4.27(2H, s), 4.15 (2H, t), 4.08 (2H, q), 3.47 (2H, s), 2.63 (2H, m), 1.14(3H, t).

[0216] STEP 7: (+/−)-Ethyl2-[10-(4-chlorobenzyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]acetate

[0217] A mixture of 0.06 g of the less mobile isomer obtained in Step 6and 0.03 g of Pd/C (5%, w/w) in 25 mL of EtOAc was shaken under 40 psiof H₂ for 3 hours. The mixture was then filtered through a pad of celiteand the filtrate was concentrated. The residue was purified by silicagel flash chromatography eluted with 6:1 hexane/EtOAc to give 0.05 g ofthe title compound as an oil.

[0218]¹H NMR (acetone-d₆) δ 7.30 (1H, d), 7.28(1H, d), 7.24 (1H, d),7.18 (2H, d), 7.09 (1H, t), 6.97 (2H, t), 4.38 (1H, m), 4.02-4.13 (4H,m), 3.78 (1H, td), 3.70 (1H, m), 2.63 (1H, dd), 2.50 (1H, dd), 2.20 (1H,m), 1.85-2.05 (3H, m), 1.18 (3H, t).

[0219] STEP 8:(+/−)-[10-(4-Chlorobenzyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]aceticacid

[0220] To a stirred solution of 0.03 g of the product from Step 7 in 2mL of THF and 1 mL of MeOH was added 1 mL of 1N LiOH solution. Themixture was stirred for 2 hours at room temperature quenched with 1 mLof AcOH and 5 mL of brine. The mixture was extracted with 20 mL of EtOAcand the extract was dried over Na₂SO₄ and concentrated. The residue wasswished from 10:1 hexane/EtOAc to give 0.02 g of the title compound as abeige solid.

[0221]¹H NMR (acetone-d₆) δ 7.30 (1H, d), 7.22 (4H, dd), 7.08 (1H, t),6.96 (2H, t), 4.30 (1H, m), 4.12 (2H, q), 3.80 (1H, td), 3.72 (1H, m),2.65 (1H, dd), 2.52 (1H, dd), 2.22 (1H, m), 1.90-2.05 (3H, m).

[0222] MS (−APCI) m/z 352.3 (M−H)⁺.

EXAMPLE 2

[0223](+/−r-[9-(4-chlorobenzyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0224] STEP 1:2-Bromo-3-(4-chlorobenzyl)-1-[2-(1,3-dioxolan-2-yl)ethyl]-1H-indole

[0225] To a vigorously stirred solution of 0.32 g of the product fromStep 2 of Example 1 in 5 mL of DMF was added sequentially 0.055 g NaH(60% in mineral oil), 0.27 mL of 2-(2-bromoethyl)-1,3-dioxolane and 0.01g of n-Bu₄NI. The mixture was stirred for 3 hours at room temperatureand then quenched with 5 mL of saturated aqueous solution of NH₄Cl and 5mL of water, and extracted with 50 mL of 1:1 hexane/EtOAc. The extractwas dried over Na₂SO₄ and concentrated. The residue was purified bysilica gel flash chromatography eluted with 9:1 hexane/EtOAc to give 0.3g of the title compound as an oil.

[0226]¹HNMR (acetone-d₆) δ 7.43 (2H, d), 7.27 (4H, dd), 7.17 (2H, t),7.00 (1H, t), 4.90 (1H, t), 4.39 (2H, t), 4.10 (2H, s), 3.96 (2H, m),3.82 (2H, m), 2.05 2H, m).

[0227] STEP 2: Ethyl(E)-5-[2-bromo-3-(4-chlorobenzyl)-1H-1-indolyl]-2-pentenoate

[0228] A solution of 0.3 g of the product from Step 1 in 8 mL of AcOHand 2 mL of water was stirred for 3 days at 45° C. The mixture wasconcentrated by co-evaporation with 2×20 mL of toluene and the residuewas dissolved in 10 mL of THF and treated with 0.35 g of(carbethoxymethylene)triphenylphosphorane. The reaction mixture wasstirred for 2 hours at 50° C., diluted with 50 mL of 5:1 hexane/EtOAc,and then filtered through a pad of silica gel. The filtrate wasconcentrated under reduced pressure and the residue was purified bysilica gel flash chromatography eluted with 9:1 hexane/EtOAc to give 0.3g of the title compound as an oil.

[0229]¹H NMR (acetone-d₆) δ 7.50 (1H, d), 7.42(1H, d), 7.25 (4H, s),7.18 (2H, t), 7.00 (1H, t), 6.90-7.02 (1H, dt), 5.78 (1H, d), 4.49 (2H,t), 4.00-4.13 (4H, m), 2.70 (2H, m), 1.20 (3H, t).

[0230] STEP 3:(+/−)-[9-(4-Chlorobenzyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0231] Starting from the product of Step 2 the title compound wasprepared as a beige solid by following the procedures described in Steps6-8 for Example 1.

[0232]¹H NMR (acetone-d₆) δ 7.42 (1H, d), 7.20-7.28 (5H, m), 7.03 (1H,t), 6.92 (1H, t), 4.16 (1H, m), 4.12 (2H, s), 4.06 (1H, m), 3.18 (1H,m), 2.75-2,90 (2H, m), 2.55 (1H, dd), 2.40 (1H, m).

[0233] MS (−APCI) m/z 338.3 (M−H)⁺.

EXAMPLE 3

[0234](+/−)-[10-[(4-chlorophenyl)sulfanyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]aceticacid

[0235] Step 1: 3-[(4-Chlorophenyl)sulfanyl]-1H-indole

[0236] To a vigorously stirred solution of 5.2 g of indole in 100 mL ofDMF was added 2.9 g of NaH (60% in mineral oil). After stirring for 15minutes, 14.4 g of bis(4-chlorophenyl) disulfide was added. Theresulting mixture was stirred for 14 hours and quenched with 15 mL ofAcOH and concentrated under reduced pressure. The residue was dissolvedin 200 mL of 1:1 hexane/EtOAc and filtered through a pad of silica gel.The filtrate was concentrated and the crude product was swished from 50mL of 10:1 hexane/EtOAc to give 8.5 g of the title compound as a whitesolid.

[0237]¹H NMR (acetone-d₆) δ 7.70 (1H, d), 7.54 (1H, d), 7.47 (1H, d),7.18-7.25 (3H, m), 7.03-7.13 (3H, m).

[0238] Step 2:(+/−)-[9-[(4-Chlorophenyl)sulfanyl]-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0239] Starting from the product obtained in Step 1, the title compoundwas synthesized following the procedures described in Step 2-8 ofExample 1.

[0240]¹H NMR (acetone-d₆) δ 7.46 (1H, d), 7.40 (11, d), 7.13-7.25 (3H,m), 7.10 (1H, t), 6.99 (2H, d), 4.33 (1H, m), 4.00 (1H, m), 3.78 (1H,m), 2.85 (1H, dd), 2.72 (1H, dd), 2.25 (1H, m), 1.95-2.10 (3H, m).

EXAMPLE 4

[0241](+/−)-[10-[(4-chlorophenyl)sulfanyl]-3-(methylsulfonyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]aceticacid

[0242] Step 1: Ethyl 6-(methylsulfanyl)-1H-2-indolecarboxylate

[0243] Starting from 3-(methylthio)aniline and ethyl2-methylacetoacetate, th title compound was prepared by following thepublished procedure for ethyl 6-methoxy-3-methyl-1H-2-indolecarboxylate(T. Gan et al, J. Org. Chem. 1997, 62, 9298-9304).

[0244]¹H NMR (acetone-d₆) δ 7.60 (1H, d), 7.40 (1H, s), 7.13 (1H, d),7.05 (dd), 4.35 (2H, q), 2.52 (3H, s), 1.35 (3H, t).

[0245] Step 2: 1H-6-Indolyl methyl sulfide

[0246] Starting from ethyl 6-(methylsulfanyl)-1H-2-indolecarboxylate,the title compound was prepared by following the publisheddecarboxylation procedure (T. Gan et al, J Org. Chem. 1997, 62,9298-9304).

[0247]¹H NMR (acetone-d₆) δ 7.50 (1H, d), 7.40 (1H, s), 7.28 (1H, m),7.00 (dd), 6.42 (1H, bs), 2.47 (3H, s).

[0248] Step 3: 1H-6-Indolyl methyl sulfone

[0249] To a solution of 0.1 g of 1H-6-indolyl methyl sulfide in 5 mL of2:1 CH₂Cl₂/MeOH cooled at 0° C. was added 0.4 g of MMPP. The resultingmixture was stirred at room temperature for 2 hours and then quenchedwith 5 mL of saturated aqueous solution of Na₂CO₃ and 5 mL of brine. Themixture was extracted with 40 mL of 1:2 hexane/EtOAc and the extract wasdried over Na₂SO₄ and concentrated. The residue was purified by silicagel flash chromatography eluted with 1:1 hexane/EtOAc to give 0.08 g ofthe title compound as a white solid.

[0250]¹H NMR (acetone-d₆) δ 8.07 (1H, s), 7.78 (1H, d), 7.65 (1H, m),7.55 (1H, d), 6.63 (1H, bs), 3.08 (3H, s).

[0251] Step 4:(+/−)-[10-[(4-chlorophenyl)sulfanyl]-3-(methylsulfonyl-6,7,8,9-tetra-hydropyrido[1,2-a]indol-9-yl]aceticacid

[0252] Starting from 1H-6-indolyl methyl sulfone, the title compound wassynthesized following the procedures described in Step 1 of Example 3and Steps 2-8 of Example 1.

[0253]¹H NMR (acetone-d₆) δ 8.08 (1H, s), 7.67 (1H, d), 7.60 (1H, d),7.20 (2H, d), 7.03 (2H, d), 4.50 (1H, m), 4.20 (1H, m), 4.83 (1H, m),3.10 (3H, s), 2.70-2.90 (2H, m), 2.30 (1H, m), 2.00-2.20 (3H, m).

EXAMPLE 5

[0254] (+/−)-[10-(4-chlorophenyl)1-(methylsulfinyl)-6,7,8,9-tetra-hydro-pyrido[1,2-a]indol-9-yl]aceticacid

[0255] Step 1: (+/−)-Ethyl 2-(4-chlorobenzyl)-3-oxobutanoate

[0256] To a suspension of NaH (1.6 g, 40 mmol) in DMF (60 mL) at 0° C.was added ethyl acetoacetate (5.7 g, 44 mmol). The mixture was stirredfor 30 minutes and p-chlorobenzyl bromide (8.2 g, 40 mmol) was added.The reaction mixture was stirred at r.t. for 2 hours and then quenchedwith water and extracted with EtOAc. The combined organic layers werewashed with water and brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel chromatography eluted with 10% EtOAcin Hexanes to provide 6.5 g of the title compound as a colorless oil.

[0257]¹H NMR (acetone-d₆) δ. 7.32-7.20 (4H, m), 4.15-4.03 (2H, m), 3.93(1H, t), 3.18-3.01 (2H, m), 2.09 (3H, s), 1.15 (3H, t).

[0258] Step 2: 2,4-Dibromo-5-(methylsulfanyl)aniline

[0259] To a solution of 3-(methylthio)aniline (4 g, 29 mmol) in 150 mLof a 5:1 THF/pyridine mixture at 0° C. was added portionwise PyH.Br₃(18.4 g, 57 mmol). The reaction mixture was stirred for 2 hours at 0°C., warmed and then filtered on a celite pad eluted with EtOAc. Theorganic layer was washed with saturated aqueous NaHSO₃, 1N HCl and brineand concentrated. The residue was purified by silica gel chromatographyeluted with 20% EtOAc in Hexanes to provide 7.7 g of the title compoundas an orange oil.

[0260]¹H NMR (acetone-d₆) δ 7.47 (1H, s), 6.76 (1H, s), 5.13 (2H, br s),2.38 (3H, s).

[0261] Step 3: Ethyl5,7-dibromo-3-(4-chlorophenyl)-4-(methylsulfanyl-1H-indole-2-carboxylate

[0262] To a suspension of the aniline of Step 2 (5.95 g, 20 mmol) in 13mL of water and 8 mL of concentrated HCl at 0° was added a NaNO₂solution (1.52 g in 3 mL of water). The mixture was stirred for 15minutes at 0° C. and was adjusted to pH 3 with the addition of NaOAc. Ina separate flask, a solution of the ester of Step 1 (5.1 g, 20 mmol) in27 mL of EtOH was treated with an aqueous solution of KOH (1.12 g in 3mL of water). The solution was then cooled to −5° C. and the diazoniumsalt was added to the alkaline solution. The pH was adjusted to 5 withNaOAc and the mixture was stirred at 0° C. for 16 hours. The reactionmixture was extracted with EtOAc and the combined organic layers weredried over MgSO₄ and concentrated.

[0263] The residue was added slowly to a 3N HCl solution in EtOH and wasstirred at 70° C. for 2 hours. EtOH was removed by evaporation and waterwas added. The aqueous layer was extracted with CH₂Cl₂ and the combinedorganic layers were dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel chromatography eluted with 25% EtOAc in Hexanesto provide 2.1 g of the title compound as an orange solid.

[0264]¹H NMR (acetone-d₆) δ 7.88 (1H, s), 7.55-7.37 (4H, m), 4.12 (2H,q), 2.01 (3H, s), 1.07 (3H, t). MS (−APCI) m/z 502.0 (M−H)⁻

[0265] Step 4: Ethyl3-(4-chlorophenyl)-4-(methylsulfanyl)-1H-indole-2-carboxylate

[0266] To a solution of the indole of step 3 (2.1 g) in 200 mL of EtOAcwas added 5% palladium on carbon (1 g). The mixture was shaken under H₂atmosphere (50 psi) for 24 hours, filtered on a silica gel pad elutedwith EtOAc and the filtrate concentrated to give the title compound as awhite solid (1.5 g) used as such.

[0267] Step 5:3-(4-Chlorophenyl)-4-(methylsulfanyl)-1H-indole-2-carboxylic acid

[0268] To a solution of the ester of Step 4 (1.5 g) in EtOH (15 mL) wasadded 1N KOH solution (13 mL). The reaction mixture was stirred atreflux for 1 hour. The organic solvent was removed by evaporation andthe aqueous solution was acidified with 3N HCl and extracted with EtOAc.The combined organic layers were dried over Na₂SO₄ and concentrated togive the title compound as a white solid (1.4 g).

[0269]¹H NMR (acetone-d₆) δ 7.41-7.35 (5H, m), 7.27 (1H, t), 6.85 (1H,d), 2.29 (3H, s).

[0270] Step 6: 3-(4-Chlorophenyl)-1H-indol-4-yl methyl sulfide

[0271] To a solution of 1.4 g of the acid of Step 5 in quinoline (10 mL)was added 100 mg of copper powder. The reaction mixture was heated toreflux and stirred for 2 hours. The copper powder was removed byfiltration and 6N HCl was added to the filtrate. The aqueous layer wasextracted with EtOAc and the combined organic layers were dried overNa₂SO₄ and concentrated. The residue was purified by silica gelchromatography eluted with 10% EtOAc in Hexanes to provide 750 mg of thetitle compound as an orange solid foam.

[0272]¹H NMR (acetone-d₆) δ 7.48 (2H, d), 7.37 (2H, d), 7.33-7.29 (2H,m), 7.13 (1H, t), 6.92 (1H, d), 2.31 (3H, s).

[0273] Step 7: 2-Bromo-3-(4-chlorophenyl)-1H-indol-4-yl methyl sulfide

[0274] To a solution of the indole of Step 6 (650 mg, 2.4 mmol) in CCl₄(15 mL) was added NBS (465 mg, 2.6 mmol). The reaction mixture washeated to 50° C. and stirred for 15 minutes. The resulting suspensionwas filtered on a SiO₂ pad eluted with 50% EtOAc in hexanes andconcentrated. The title compound was obtained in a quantitative yield asa brownish solid foam used as such.

[0275] Step 8: Ethyl4-[2-bromo-3-(4-chlorophenyl)-4-(methylsulfanyl-1H-indol-1-yl]butanoate

[0276] To a solution of the indole of Step 7 (525 mg, 1.5 mmol) in DMF(5 mL) was added NaH (72 mg, 1.8 mmol, 60% in oil) at 0° C. The reactionmixture was stirred at 0° C. for 15 minutes and tetra-n-butylammoniumiodide (180 mg) was added, followed by the addition of ethyl4-bromobutyrate (406 mg, 2.1 mmol). The resulting mixture was stirredfor 1 hour 30 minutes at r.t., quenched with saturated aqueous NH₄Cl andextracted with EtOAc. The combined organic layers were washed with waterand brine, dried over Na₂SO₄ and concentrated. The residue was purifiedby silica gel chromatography eluted with 10% EtOAc in Hexanes to provide330 mg of the title compound as a pale yellow oil.

[0277]¹H NMR (acetone-d₆) δ 7.45-7.38 (5H, m), 7.23 (1H, t), 6.92 (1H,d), 4.41 (2H, t), 4.12 (2H, q), 2.42 (2H, t), 2.29 (3H, s), 2.14-2.04(2H, m), 1.18 (3H, t).

[0278] Step 9:4-[2-Bromo-3-(4-chlorophenyl)-4-(methylsulfanyl-1H-indol-1-yl]butanal

[0279] To a solution of the ester of Step 8 (330 mg, 0.7 mmol) in Et₂O(5 mL) at −78° C. was added DIBAL (2 mL, 1M solution in hexanes). Thereaction mixture was stirred at −78° C. for 30 minutes and then quenchedwith 0.5 mL of acetone. 1N HCl was added, the phases were separated andthe aqueous layer was extracted with Et₂O. The combined organic layerswere dried over MgSO₄ and concentrated. The residue was purified bysilica gel chromatography eluted with 40% EtOAc in Hexanes to provide270 mg of the title compound as a pale yellow solid.

[0280]¹H NMR (acetone-d₆) δ 9.75 (1H, s), 7.44-7.38 (5H, m), 7.21 (1H,t), 6.90 (1H, d), 4.37 (2H, t), 2.62 (2H, t), 2.29 (3H, s), 2.11-2.02(2H, m).

[0281] Step 10: Ethyl (2E,Z)-6-[2-bromo-3-(4-chlorophenyl)-4-(methylsulfanyl-1H-indol-1-yl]-2-hexenoate

[0282] To a solution of the aldehyde of Step 9 (265 mg, 0.6 mmol) in THF(10 mL) at r.t. was added (ethoxycarbonylmethylene)triphenylphosphorane(500 mg, 1.4 mmol). The reaction mixture was stirred at r.t. for 30minutes, filtered on a SiO₂ pad eluted with 30% EtOAc in hexanes andconcentrated to give 300 mg of the title compound as a pale yellow oil.

[0283]¹H NMR (acetone-d₆) δ 7.44-7.37 (5H, m), 7.17 (1H, t), 6.95-6.87(2H, m), 5.84 (1H, d), 4.38 (2H, t), 4.12 (2H, q), 2.36 (2H, q), 2.29(3H, s), 2.06-1.96 (2H, m), 1.21 (3H, t). MS (+APCI) m/z 413.1, 415.1(M−Br)⁺

[0284] Step 11: Ethyl(2-E,Z)-(10-(4-chlorophenyl)-1-(methylsulfanyl)-7,8-dihydro-pyrido[1,2-a]indol-9(6H)-ylidene)ethanoate

[0285] To a solution of the indole of Step 10 (270 mg, 0.6 mmol) in DMF(8 mL) at r.t. was added tetra-n-butylammonium iodide (164 mg, 0.6mmol), palladium(II) acetate (65 mg) and 200 μL of triethylamine. Thereaction mixture was heated to 75° C. and stirred for 2 hours, cooled,filtered on a SiO₂ pad eluted with 50% EtOAc in hexanes and the filtrateconcentrated to give 300 mg of the desired compound used as such.

[0286] Step 12: (+/−)-Ethyl[10-(4-chlorophenyl)-1-(methylsulfanyl)-6,7,8,9-tetrahydro-pyrido[1,2-a]indol-9-yl]acetate

[0287] To absolution of the indole of Step 11 (300 mg) in EtOAc (15 mL)was added 5% palladium on carbon (100 mg). The mixture was shaken underH₂ atmosphere (50 psi) for 12 hours, filtered on a silica gel pad elutedwith EtOAc and the filtrate concentrated. The residue was purified bysilica gel chromatography eluted with 30% EtOAc in Hexanes to provide170 mg of the title compound as a pale yellow syrup used as such.

[0288] Step 13: (+/−)-Ethyl[10-(4-chlorophenyl)-1-(methylsulfinyl)-6,7,8,9-tetrahydro-pyrido[1,2-a]indol-9-yl]acetate

[0289] To a solution of the sulfide of Step 12 (110 mg, 0.1 mmol) in 8ml of CH₂Cl₂/MeOH (10:1) at 0° C. was added MMPP (79 mg, 0.1 mmol). Thereaction mixture was stirred at 0° C. for 1 hour and then quenched witha saturated aqueous solution of NaHCO₃ and extracted with EtOAc. Theorganic layer was dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel chromatography eluted with 70% EtOAc in Hexanesto provide 40 mg of the less polar diastereomer and 38 mg of the morepolar diastereomer as a white solid.

[0290] Less polar diastereomer: ¹H NMR (acetone-d₆) δ 7.70 (1H, dd),7.58 (1H, dd), 7.56-7.36 (5H, m), 4.37-4.32 (1H, m), 4.15-4.05 (1H, m),3.95 (2H, q), 3.86-3.78 (1H, m), 2.40 (1H, dd), 2.25-2.03 (4H, m), 2.08(3H, s), 1.95-1.86 (1H, m), 1.10 (3H, t).

[0291] More polar diastereomer: ¹H NMR (acetone-d₆) δ 7.75 (1H, dd),7.56 (1H, dd), 7.52-7.34 (5H, m), 4.39-4.34 (1H, m), 4.07-3.98 (3H, m),3.51-3.46 (1H, m), 2.67-2.53 (2H, m), 2.40 (3H, s), 2.31-2.22 (1H, m),2.11-1.88 (3H, m), 1.12 (3H, t).

[0292] Step 14:(+/−)-[10-(4-Chlorophenyl)-1-(methylsulfinyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]aceticacid

[0293] To a solution of the ester of Step 13 in a THF/MeOH (3:1) mixtureat r.t. was added 1N LiOH (aqueous solution). The reaction mixture wasstirred at r.t. for 2 hours and AcOH (0.5 mL) and brine (5 mL) wereadded. The aqueous layer was extracted with EtOAc and the combinedorganic layers were dried over Na₂SO₄ and concentrated. The residue wasswished in EtOAc/hexanes to give the desired acid as a white solid. Eachisomer from Step 13 was hydrolyzed under these conditions. From the lesspolar diastereomer of Step 13: ¹H NMR (methanol-d₄) δ 7.65 (1H, d), 7.61(1H, d), 7.51-7.35 (5H, m), 4.37-4.29 (1H, m), 4.09-4.02 (1H, m),3.79-3.71 (1H, m), 2.40 (1H, dd), 2.24 (3H, s), 2.23-1.91 (5H, m). MS(−APCI) m/z 400.2 M-H)⁺.

[0294] From the more polar diastereomer of Step 13: ¹H NMR (methanol-d₄)δ 7.67 (1H, d), 7.60 (1H, d), 7.47-7.28 (5H, m), 4.37-4.31 (1H, m),4.08-3.96 (1H, m), 3.53-3.47 (m, 1H), 2.56 (3H, s), 2.54-1.98 (6H, m).MS (−APCI) m/z 400.2 (M−H)⁻.

EXAMPLE 6

[0295](+/−)-[10-(4-chlorobenzyl)-1-(methylsulfinyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]aceticacid

[0296] Step 1: 4-Bromo-1H-indole

[0297] 2-Bromo-6-nitrotoluene (3.2 g, 15 mmol), N,N-dimethylformamidedimethyl acetal (5.4 g, 45 mmol) and pyrrolidine (1.1 g, 15 mmol) werecombined in 30 mL of DMF and heated at 110° C. The reaction mixture wasstirred at 110° C. for 2.5 hours and then water was added. The aqueouslayer was extracted with Et₂O and the combined organic layers werewashed with water and brine, dried over MgSO₄ and concentrated. Thebrown syrup was dissolved in 80% aqueous AcOH (80 mL) and heated to 75°C. Zn powder (8.5 g), 130 mmol) was then added portionwise over 1 hourand the temperature was raised to 85° C. for 2 hours. The reactionmixture was filtered and water was added. The aqueous layer wasextracted with Et₂O and the combined organic layers were washed withsaturated aqueous sodium bicarbonate and water, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatographyeluted with 20% EtOAc in Hexanes to provide 2 g of the title compound asa greenish oil used as such.

[0298] Step 2: 4-Bromo-1-(triisopropylsilyl)-1H-indole

[0299] To a solution of the indole of Step 1 (8.9 g, 45 mmol) in DMF(150 mL) at 0° C. was added portionwise NaH (2.2 g, 55 mmol, 60% inoil). The reaction mixture was stirred for 30 minutes at 0° C. andtriisopropylsilyl chloride (10.5 g, 55 mmol) was added. The reactionmixture was stirred for 30 minutes and 400 mL of Et₂O was added. Thereaction was quenched with saturated aqueous NH₄Cl and extracted withEt₂O. The combined organic layers were washed with water and brine,dried over Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography eluted with 100% Hexanes to provide 16 g of the titlecompound as a white solid.

[0300]¹H NMR (acetone-d₆) δ 7.61 (1H, d), 7.47 (1H, d), 7.27 (1H, d),7.08 (1H, t), 6.65 (1H, d); 1.85-1.75 (3H, m), 1.14 (18H, d).

[0301] Step 3: 4-(Methylsulfanyl-1-(triisopropylsilyl)-1H-indole

[0302] To a solution of the indole of Step 2 (2.9 g, 8 mmol) in Et₂O (50mL) at −78° C. was added t-BuLi (11 mL, 18 mmol). The reaction mixturewas stirred for 10 minutes at −78° C. and dimethyl disulfide (2.3 g, 25mmol) was added. The reaction mixture was stirred for 30 minutes and thereaction was quenched with water. The phases were separated and theaqueous layer was extracted with Et₂O. The combined organic layers weredried over Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography eluted with 5% EtOAc in Hexanes to provide 2.5 g ofthe title compound as a colorless oil.

[0303]¹HNMR (acetone-d₆) δ 7.43-7.36 (2H, m), 7.11 (1H, t), 6.97 (1H,d), 6.68 (1H, d), 2.53 (3H, s), 1.82-1.73 (3H, m), 1.14 (18H, d).

[0304] Step 4: 3-Bromo-1-(triisopropylsilyl)-1H-indol-4-yl methylsulfide

[0305] To a solution of the indole of Step 3 (500 mg, 1.6 mmol) in THF(10 mL) at −78° C. was added NBS (280 mg, 1.6 mmol). The reactionmixture was stirred for 30 minutes and the solvent was removed byevaporation. The residue was purified by silica gel chromatographyeluted with 5% EtOAc in Hexanes to provide 540 mg of the title compoundas a pale yellow oil.

[0306]¹H NMR (acetone-d₆) δ 7.45-7.36 (2H, m), 7.13 (1H, t), 6.96 (1H,d), 2.52 (3H, s), 1.82-1.73 (3H, m), 1.14 (18H, d).

[0307] Step 5: 3-(4-chlorobenzyl)-1-(triisopropylsilyl)-1H-indol-4-ylmethyl sulfide

[0308] To a solution of the indole of Step 4 (2.4 g, 6 mmol) in Et₂O (50mL) at −78° C. was added t-BuLi (7 mL, 12 mmol). The reaction mixturewas stirred for 10 minutes at −78° C. and p-chlorobenzyl bromide (3.6 g,18 mmol) was added. The reaction mixture was stirred for 2 hours at r.t.and was quenched with saturated aqueous NH₄Cl. The phases were separatedand the aqueous layer was extracted with Et₂O. The combined organiclayers were dried over Na₂SO₄ and concentrated. The residue was purifiedby silica gel chromatography eluted with 5% EtOAc in Hexanes to provide1.9 g of the title compound as a pale yellow oil used as such.

[0309] Step 6: 3-(4-Chlorobenzyl)-1H-indol-4-yl methyl sulfide

[0310] To a solution of the indole of Step 5 (1.9 g, 4.3 mmol) in THF(20 ml at 0° C. was added 1M TBAF (7 mL, 6 mmol). The reaction mixturewas stirred for 1 minutes at 0° C. and water was added. The phases wereseparated and the aqueous layer was extracted with Et₂O. The combinedorganic layers were dried over MgSO and concentrated The residue waspurified by silica gel chromatography eluted with 20% EtOAc in Hexanesto provide 700 mg of the title compound as a pale yellow oil.

[0311]¹H NMR (acetone-d₆) δ 7.28-7.20 (5H, m); 7.08 (1H, t), 6.98 (11,s), 6.87 (1H, d), 4.41 (2H, s), 2.41 (3H, s).

[0312] Step 7: 2-Bromo-3-(4-chlorobenzyl)-1H-indol-4-yl methyl sulfide

[0313] To a solution of the indole of Step 6 (700 mg, 2.4 mmol) in CCl₄(15 mL) was added NBS (475 mg, 2.7 mmol). The reaction mixture washeated to 50° C. and stirred for 20 minutes. The resulting suspensionwas filtered on SiO₂ pad eluted with 50% EtOAc in hexanes andconcentrated. The title compound was obtained in quantitative yield as abrownish solid foam and used as such.

[0314] Step 8: Ethyl4-[2-bromo-3-(4-chlorobenzyl)-4-(methylsulfanyl)-1H-indol-1-yl]butanoate

[0315] To a solution of the indole of Step 7 (800 mg, 2.4 mmol) in DMF(15 mL) was added NaH (136 mg, 3.4 mmol, 60% in oil) at 0° C. Thereaction mixture was stirred at 0° C. for 15 minutes andtetra-n-butylammonium iodide (300 mg) was added, followed by theaddition of ethyl 4-bromobutyrate (663 mg, 3.3 mmol). The resultingmixture was stirred for 2 h at r.t., quenched with saturated aqueousNH₄Cl and extracted with EtOAc. The combined organic layers were washedwith water and brine, dried over Na₂SO₄ and concentrated. The residuewas purified by silica gel chromatography eluted with 20% EtOAc inHexanes to provide 690 mg of the title compound as a brown oil.

[0316]¹H NMR (acetone-d₆) δ 7.37 (1H, d), 7.25-7.16 (5H, m), 6.93 (1H,d), 4.45 (1H, s), 4.38 (2H, d), 4.07 (2H, q), 2.42-2.37 (5H, m),2.10-2.01 (2H, m), 1.18 (3H, t).

[0317] Step 9:4-[2-Bromo-3-(4-chlorobenzyl-4-(methylsulfanyl-1H-indol-1-yl]butanal

[0318] To a solution of the ester of Step 8 (685 mg, 1.4 mmol) in Et₂O(15 mL) at −78° C. was added DIBAL (2.5 mL, 1M solution in hexanes). Thereaction mixture was stirred at −78° C. for 30 minutes, quenched with0.5 mL of acetone and 1N HCl was added. The phases were separated andthe aqueous layer was extracted with Et₂O. The combined organic layerswere dried over MgSO₄ and concentrated to give 575 mg of the desiredcompound as a brownish solid used as such.

[0319] Step 10: Ethyl (2E,Z)-6-[2-bromo-3-(4-chlorobenzyl)-4-(methylsulfanyl)-1H-indol-1-yl]-2-hexenoate

[0320] To a solution of the aldehyde of Step 9 (575 mg, 1.3 mmol) in THF(15 mL) at r.t. was added (ethoxycarbonylmethylene)triphenylphosphorane(920 mg, 2.6 mmol). The reaction mixture was stirred at r.t. for 2hours, then filtered on a SiO₂ pad eluted with 30% EtOAc in hexanes andconcentrated. The residue was purified by silica gel chromatographyeluted with 20% EtOAc in Hexanes to provide 520 mg of the title compoundas brownish syrup used as such.

[0321] Step 11: Ethyl (2E,Z)-(10-(4-chlorobenzyl)-1-(methylsulfanyl)-7,8-dihydro-pyrido[1,2-a]indol-9(6H)-ylidene)ethanoate

[0322] To a solution of the indole of Step 10 (520 mg, 1 mmol) in DMP(12 mL) at r.t. was added tetra-n-butylammonium iodide (300 mg, 1 mmol),palladium(II) acetate (100 mg) and 400 μL of triethylamine. The reactionmixture was heated to 75° C. and stirred for 2 hours. The reactionmixture was cooled, filtered on a SiO₂ pad eluting with 50% EtOAc inhexanes and concentrated. The residue was purified by silica gelchromatography eluted with 20% EtOAc in Hexanes to provide 420 mg of thetitle compound as a pale yellow solid.

[0323] Step 12: (+/−)-Ethyl[10-(4-chlorobenzyl)-1-(methylsulfanyl)-6,7,8,9-tetrahydro-pyrido[1,2-a]indol-9-yl]acetate

[0324] To a solution of the indole of Step 11 (420 mg) in EtOAc (20 mL)was added 5% Palladium on carbon (150 mg). The mixture was shaken underH₂ atmosphere (50 psi) for 4 days, filtered on a silica gel pad elutedwith EtOAc and concentrated. The residue was purified by silica gelchromatography eluted with 20% EtOAc in Hexanes to provide 275 mg of thetitle compound as a pale yellow syrup.

[0325]¹H NMR (acetone-d₆) δ 7.28-7.06 (6H, m), 6.91 (1H, d), 4.43 (2H,dd), 4.33-4.28 (1H, m), 4.06 (2H, q), 3.77 (1H td), 3.65-3.61 (1H, m),2.59 (1H, dd), 2.35 (3H, s), 2.40-2.02 (3H, m), 1.97-1.85 (2H, m), 1.18(3H, t).

[0326] Step 13: (+/−)-Ethyl[10-(4-chlorobenzyl)-1-(methylsulfinyl)-6,7,8,9-tetrahydro-pyrido[1,2-a]indol-9-yl]acetate

[0327] To a solution of the sulfide of Step 12 (270 mg, 0.6 mmol) in 30ml of CH₂Cl₂/MeOH (10:1) mixture at 0° C. was added MMPP (312 mg, 0.6mmol). The reaction mixture was stirred at 0° C. for 30 minutes and thenquenched with saturated aqueous NaHCO₃ and extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel chromatography eluted with 70% EtOAcin Hexanes to provide 210 mg as a white solid.

[0328] (Mixture of diastereomers) ¹H NMR (acetone-d₆) δ 7.71-7.65 (1H,m), 7.57-7.52 (1H, m), 7.38-7.22 (3H, m), 7.12-7.03 (2H, m), 4.47-3.88(6H, m), 2.75-1.97 (10H, m), 1.21-1.04 (3H, m).

[0329] Step 14:(+/−)-[10-(4-Chlorobenzyl)-1-(methylsulfinyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]aceticacid

[0330] To a solution of the ester of Step 13 (70 mg) in a THF/MeOH (3:1)mixture at r.t. was added 1N LiOH (aqueous solution). The reactionmixture was stirred at r.t. for 2 h and AcOH was added. The aqueouslayer was extracted with EtOAc and the combined organic layers weredried over Na₂SO₄ and concentrated. The residue was swished inEtOAc/MeOH to give 35 mg of the desired acid as a white solid.

[0331] Mixture of diastereomers: ¹H NMR (acetone-d₆) δ 7.58-7.49 (2H,m), 7.29-7.23 (3H, m), 7.08-6.97 (2H, m), 4.39-3.52 (5H, m), 2.28-1.68(9H, m).

[0332] MS (−APCI) m/z 414.1 (M−H)⁻.

EXAMPLE 7

[0333](+/−)-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0334] Step 1: 2-Bromo-1-(bromomethyl)-4-fluorobenzene

[0335] To a solution of 2-bromo-4-fluorotoluene (50 g, 265 mmol) in CCl₄(1L) was added NBS (52 g, 291 mmol) and 300 mg of benzoyl peroxide. Themixture was heated to reflux and stirred for 30 minutes under a sunlamp. The reaction mixture was cooled and filtered on a SiO₂ pad elutedwith hexanes. The filtrate was concentrated to give 70 g of the titlecompound as a colorless oil and used as such.

[0336] Step 2: 2-Bromo-4-fluorobenzaldehyde

[0337] To a solution of the benzyl bromide of Step 1 (59 g, 220 mmol) indioxane (500 mL) at r.t. was added N-methylmorpholine N-oxidemonohydrate (89 g, 660 mmol). The reaction mixture was stirred for 1hour at 70° C. and poured into a mixture of saturated aqueous NH₄Cl andEtOAc. The phases were separated and the aqueous layer was extractedwith EtOAc. The combined organic layers were washed with water, driedover Na₂SO₄ and concentrated to give 44 g of the title compound as awhite solid and used as such.

[0338] Step 3:Methyl(2E,Z)-2-azido-3-(2-bromo-4-fluorophenyl)-2-propenoate

[0339] To a mixture of NaOMe (36 mL, 25% solution in MeOH) and MeOH (60mL) at −10° C. was slowly added (over 10 minutes) a mixture of thealdehyde of Step 2 (8 g, 39 mmol) and methyl azidoacetate (18.4 g, 160mmol) in MeOH (15 mL). The mixture was stirred for 12 hours at 0° C. andthen poured into 120 g of ice. The precipitate was filtered and dried byHi-vacuum (overnight) to give 6.3 g of the title compound as a yellowsolid and used as such.

[0340] Step 4: Methyl 4-bromo-6-fluoro-1H-indole-2-carboxylate

[0341] To 160 mL of boiling xylene was slowly added (over 2 hours timeperiod) a solution of the azidoester of Step 3 (6.3 g) in xylene (100mL). The reaction mixture was stirred at reflux for 4 hours and cooled.The xylene was removed by evaporation and the yellow solid was swishedin toluene to give 3.9 g of the title compound as a white solid.

[0342]¹H NMR (acetone-d₆) δ 11.41 (1H, br s), 7.31 (1H, dd), 7.28 (1H,dd), 7.15 (1H, s), 3.93 (3H, s).

[0343] Step 5: (+/−)-Methyl8-bromo-6-fluoro-1-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indole-2-carboxylate

[0344] To a suspension of the indole of Step 4 (4 g, 15 mmol) in amixture of 10:1 toluene/THF (100 mL) at r.t. was added potassiumt-butoxide (15 mL of a 1M solution in THF). The reaction mixture wasstirred for 2 minutes and methyl acrylate (2.5 g, 30 mmol) was added.The mixture was stirred at reflux for 5 hours and cooled to r.t. Then 1NHCl was added to acidify to pH 3 and the reaction mixture was extractedwith EtOAc and the combined organic layers were concentrated. Theresidue was swished in EtOAc/Hexanes to give 4 g of the desired compoundas a pale yellow solid.

[0345]¹H NMR (acetone-d₆) δ 7.54 (1H, dd), 7.36 (1H, dd), 7.04 (1H, s),4.91-4.83 (2H, m), 4.48-4.43 (1H, m), 3.77 (3H, s).

[0346] Step 6: 8-Bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one

[0347] To a solution of the ketoester of Step 5 (4 g) in EtOH (150 mL)r.t. was added 40 mL of concentrated HCl. The reaction mixture wasstirred at reflux for 1 hour and water was added. The aqueous layer wasextracted with CH₂Cl₂ and the combined organic layers were concentratedThe residue was swished in EtOAc/Hexanes to provide 2.9 g of the titlecompound as a pale yellow solid.

[0348]¹H NMR (acetone-d₆) δ 7.45 (1H, dd), 7±30 (1H, dd), 6;85 (1H, s),4.57 (2H, t), 3.23 (2H, t).

[0349] Step 7: (+/−)-Methyl(8-bromo-6-fluoro-1-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[0350] To a suspension of the ketone of Step 6 (800 mg, 3 mmol) in THF(10 mL) was added methyl bromoacetate (2.3 g, 15 mmol) and 1 g ofZn-copper couple. The reaction mixture was put in a sonicator at r.t.until an exotherm was observed. The reaction flask was cooled in an icebath to keep the internal temperature below 50° C. and the mixture wasstirred at r.t. for 1 hour. The reaction mixture was poured into a 2:1mixture of saturated aqueous NH₄Cl/EtOAc (100 mL) and filtered on paper.The filtrate was extracted with EtOAc, the combined organic layers werewashed with brine and water, dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel chromatography eluted with 35% EtOAcin Hexanes to provide 780 mg of the title compound as a pale yellow oil.

[0351]¹H NMR (acetone-d₆) δ 7.21 (1H, dd), 7.11 (1H, dd), 6.35 (1H, s),4.71 (1H, s), 4.29-4.20 (2H, m), 3.70 (3H, s), 3.14 (1H, d), 3.05 (1H,d), 3.02-2.90 (1H, m), 2.81-2.74 (1H, m).

[0352] Step 8: (+/−)-Methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[0353] To dry CH₃CN (2.3 g, 56 mmol) at r.t. was added NaI (8.4 g, 56mmol) and trimethylsilyl chloride (6.1 g, 56 mmol). Then a solution ofthe alcohol of Step 7 (1.9 g, 5.6 mmol) in Et₂O (60 mL) was slowlyadded. The reaction mixture was stirred for 5 minutes at r.t. and pouredinto a 1:1 mixture of saturated aqueous NaHCO_(3/10)% aqueous Na₂S₂O₃(100 mL) at 0° C. The phases were separated and the aqueous layer wasextracted with Et₂O. The combined organic layers were washed with brine,dried over Na₂SO₄ and concentrated. The desired compound was obtained asa brown solid (1.3 g).

[0354]¹HNMR (acetone-d₆) δ 7.12 (1H, d), 7.04 (1H, dd), 6.15 (1H, s),4.26-4.18 (1H, m), 4.12-4.06 (1H, m), 3.72-3.67 (1H, m), 3.69 (3H, s),2.93-2.82 (2H, m), 2.71 (1H, dd), 2.37-2.31 (1H, m).

[0355] Step 9: (+/−)-Methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0356] To a solution of bis(4-chlorophenyl) disulfide (1.38 g, 4.8 mmol)in 1,2-dichloroethane (25 mL) at 0° C. was added sulfuryl chloride (536mg, 4 mmol). The mixture was stirred for 1 hour at r.t. and was added toa solution of the ester of Step 8 (1.3 g, 4 mmol) in DMF (25 mL) at r.t.The reaction mixture was stirred for 10 minutes and saturated aqueousNaHCO₃ was added. The aqueous layer was extracted with EtOAc, and thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatographyeluted with 20% EtOAc in Hexanes to provide 1.2 g of the title compoundas pale yellow foam.

[0357]¹H NMR (acetone-d₆) δ 7.30 (1H, dd), 7.24 (2H, d), 7.13 (1H, dd),7.03 (2H, d), 4.41-4.34 (1H, m), 4.27-4.20 (1H, m), 3.89-3.82 (1H, m),3.60 (3H, s), 3.18-3.12 (1H, m), 3.05-2.95 (1H, m), 2.78-2.70 (1H, m),2.51-2.43 (1H, m).

[0358] Step 10:(+/−)-[8-Bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0359] To a solution of the ester of Step 9 (80 mg) in a 3:1 mixture ofTHF/MeOH (3 mL) at r.t. was added 1N LiOH (1 mL, aqueous solution). Thereaction mixture was stirred at r.t. for 2 h and AcOH (0.5 mL) and brine(5 mL) were added. The aqueous layer was extracted with EtOAc and thecombined organic layers were dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel chromatography eluted with 40%EtOAc/hexane containing 1% AcOH to provide 70 mg of the title compoundas a pale yellow solid.

[0360]¹H NMR (acetone-d₆) δ 7.36 (1H, dd), 7.24 (2H, d), 7.13 (1H, dd),7.05 (2H, d), 4.43-4.35 (1H, m), 4.28-4.21 (1H, m), 3.87-3.81 (1H, m),3.20 (1H, dd), 3.07-2.98 (1H, m), 2.71 (1H, dd), 2.54-2.45 (1H, m).

[0361] MS (−APCI) m/z 453.9 M−H)⁻.

EXAMPLE 7A

[0362](+)-[8-bromo-9-[(4-chloro-phenyllsvulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0363] Step 1:(+/−)-(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid

[0364] To a solution of (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (11 g)in a THF/MeOH (3:1) mixture at r.t. was added 1N LiOH (50 mL, aqueoussolution). The reaction mixture was stirred at r.t. for 12 hours andAcOH (5 mL) and brine (100 mL) were added. The aqueous layer wasextracted with EtOAc and the combined organic layers were dried overNa₂SO₄ and concentrated to provide the title compound as a white solid.

[0365]¹H NMR (acetone-d₆) δ 7.15 (1H, dd), 7.07 (1H, dd), 6.21 (1H, s),4.28-4.22 (1H, m), 4.14-4.08 (1H, m), 3.79-3.71 (1H, m), 2.98-2.78 (2H,m), 2.73 (1H, dd), 2.42-2.37 (1H, m).

[0366] Step 2:(4S)-4-benzyl-3-[(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetyl]-1,3-oxazolidin-2-one

[0367] To a solution (S)-(−)-4-benzyl-2-oxazolidinone (7.8 g, 43.8 mmol)in THF (300 mL) at −78° C. was slowly added 1.6M n-butyllithium (27.3mL, 43.8 mmol). The mixture was stirred for 30 minutes at −78° C. and amixture of the compound of Step 1 (10.5 g, 33.7 mmol) and1,1′-carbonyldiimidazole (6 g, 37 mmol) in THF (100 mL) was added. Themixture was stirred for 30 minutes at −78° C. and then warmed to −30° C.and stirred for 2 hours. The reaction was quenched with saturated NH₄Cl,the phases were separated and the aqueous layer was extracted withEtOAc. The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated. The residue was purified by silica gelchromatography eluted with 10% EtOAc in Toluene, which permitted theseparation of the two diastereomers. Both isomers were obtained as anyellow solid with diastereomeric excess>95%.

[0368] Isomer A (less polar isomer): ¹H NMR (DMSO-d₆) δ 7.36-7.11 (7H,m), 6.12 (1H, s), 4.77-4.72 (1H, m), 4.37(1H, t), 4.22-4.15 (2H, m),4.08-4.02 (1H, m), 3.77-3.71 (1H, m), 3.33-3.18 (2H, m), 3.08-2.93 (2H,m), 2.89-2.80 (1H, m), 2.35-2.25 (1H, m).

[0369] Isomer B (more polar isomer): ¹H NMR (DMSO-d₆) δ 7.35-7.12 (7H,m), 6.15 (1H, s), 4.78-4.68 (1H, m), 4.35 (1H, t), 4.22-4.12 (2H, m),4.10-4.02 (1H, m), 3.78-3.72 (1H, m), 3.42-3.28 (1H, m), 3.15 (1H, dd),3.09-2.98 (2H, m), 2.87-2.80 (1H, m), 2.30-2.21 (1H, m). [α]_(D)=+101°,c=0.1 in acetone.

[0370] Step 3:(4S)-4-benzyl-3-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetyl)-1,3-oxazolidin-2-one

[0371] Starting from isomer B (the more polar isomer) obtained in Step 2(5.0 g, 10.6 mmol) the title compound was synthesized as described inStep 9 of Example 7 as a yellow solid, and used as such.

[0372] Step 4:(+)-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0373] To a solution of the product of Step 3 (6.1 g) in THF (120 mL) at0° C. were added a solution of LiOH (600 mg in 30 mL of H₂O) and H₂O₂30% (6 mL). The reaction mixture was stirred at 0° C. for 1 hour and thereaction was quenched with 1M Na₂SO₃. The mixture was acidified to pH 4with 1M NaHSO₄. The aqueous layer was extracted with EtOAc and thecombined organic layers were dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel chromatography eluted withEtOAc/hexanes/AcOH (30:70:1) to provide the title compound as a paleyellow solid. [α]_(D)+87°, c=0.1 in MeOH.

EXAMPLE 8

[0374](+/−)-[1-bromo-10-[(4-chlorophenyl)sulfanyl]-3-fluoro-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]aceticacid

[0375] Step 1: Methyl4-bromo-3-[(4-chlorophenyl)sulfanyl]-6-fluoro-1H-indole-2-carboxylate

[0376] To a solution of bis(4-chlorophenyl) disulfide (4 g, 14 mmol) inDCE at 0° C. (30 mL) was slowly added sulfuryl chloride (1.8 g, 14mmol). After 1 hour of stirring the mixture was added to a solution ofmethyl 4-bromo-6-fluoroindole-2-carboxylate (2.5 g, 9 mmol) in DMF (30mL) at r.t. The reaction mixture was stirred for 2 hours and saturatedaqueous NaHCO₃ was added. The phases were separated and the aqueouslayer was extracted with EtOAc. The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated. The residue was swishedin EtOAc to give 1.5 g of desired compound as a white solid.

[0377]¹H NMR (acetone-d₆) δ 7.38 (1H, dd), 7.31-7.21 (3H, m), 7.07 (2H,d), 3.88 (3H, s).

[0378] Step 2: Methyl4-bromo-3-[(4-chlorophenyl)sulfanyl]-1-(4-ethoxy-4-oxobutyl)-6-fluoro-1H-indole-2-carboxylate

[0379] To a solution of the indole of Step 1 (500 mg, 1.2 mmol) in DMF(10 mL) at 0° C. was added NaH (63 mg, 1.6 mmol, 60% in oil). Thereaction mixture was stirred at 0° C. for 15 minutes andtetra-n-butylammonium iodide (300 mg) was added, followed by theaddition of ethyl 4-bromobutyrate (360 mg, 1.8 mmol). The resultingmixture was stirred for 3 hours at r.t., quenched with saturated aqueousNH₄Cl and extracted with EtOAc. The combined organic layers were washedwith water and brine, dried over Na₂SO₄ and concentrated. The residuewas purified by silica gel chromatography eluted with 30% EtOAc inHexanes to provide 500 mg of the title compound as a solid.

[0380]¹H NMR (acetone-d₆) δ 7.64 (1H, dd), 7.28 (1H, dd), 7.23 (2H, d),7.07 (2H, d), 4.55 (2H, t), 4.08 (2H, q), 3.91 (3H, s), 2.42 (2H, t),2.18-2.09 (2H, m), 1.10 (3H, t).

[0381] Step 3: (+/−)-Ethyl1-bromo-10-[(4-chlorophenyl)sulfanyl]-3-fluoro-9-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxylate

[0382] To a solution of the indole of Step 2 (460 mg, 0.9 mmol) in THF(100 mL) at 0° C. was added potassium t-butoxide (1.2 mL of a 1Msolution in THF The reaction mixture was stirred for 2 hours at 0° C.and 1N HCl was added. The phases were separated and the aqueous layerwas extracted with EtOAc. The combined organic layers were dried overNa₂SO₄ and concentrated to give 400 mg of a pale yellow solid used assuch.

[0383] Step 4:1-Bromo-10-[(4-chlorophenyl)sulfanyl]-3-fluoro-7,8-dihydropyrido[1,2-a]indol-9(6H)-one

[0384] To a solution of the ketoester of Step 3 (400 mg) in EtOH (10 mL)at r.t. was added 3 mL of concentrated HCl. The reaction mixture wasstirred at reflux for 4 hours, cooled and poured into saturated aqueousNaHCO₃. The aqueous layer was extracted with EtOAc and the combinedorganic layers were dried over Na₂SO₄ and concentrated. The residue wasswished in EtOAc to provide 220 mg of the title compound as a yellowsolid.

[0385]¹HNMR (acetone-d₆) δ 7.51 (1H, dd), 7.30 (1H, dd), 7.18 (2H, d),7.05 (2H, d), 4.46 (2H, t), 2.75 (2H, t), 2.53-2.43 (2H, m).

[0386] MS (+APCI) m/z 425.9 (M+H)⁺.

[0387] Step 5: (+/−)-Methyl[1-bromo-10-[(4-chlorophenyl)sulfanyl]-3-fluoro-9-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]acetate

[0388] To a boiling suspension of 300 mg of Zn-copper couple in 4 mL ofTHF was added dropwise methyl bromoacetate (720 mg, 4.7 mmol). Thesuspension was stirred at reflux for 30 minutes and a solution of theketone of Step 4 (200 mg, 0.5 mmol) in THF (1 mL) was added. Thereaction mixture was stirred at reflux for 5 h and saturated aqueousNH₄Cl solution was added and extracted with EtOAc. The combined organiclayers were washed with brine and water, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatographyeluted with 20% EtOAc in Hexanes to provide 106 mg of the title compoundas a pale brown solid.

[0389]¹H NMR (acetone-d₆) δ 7.38 (1H, dd), 7.21 (2H, d), 7.15 (1H, dd),6.97 (2H, br d), 4.54 (1H, br s), 4.36-4.28 (1H, m), 4.12-4.01 (1H, m),3.79-3.71 (1H, m), 3.41 (3H, br s), 3.18-3.07 (1H, m), 2.49-2.05 (4H,m).

[0390] Step 6: (+/−)-Methyl[1-bromo-10-[(4-chlorophenyl)sulfanyl]-3-fluoro-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]acetate

[0391] To a solution of the alcohol of Step 5 (70 mg, 0.1 mmol) inCH₂Cl₂ (2 mL) at r.t. was added 0.25 mL of trifluoroacetic acid and 0.1mL of triethylsilane. The reaction mixture was stirred at r.t. for 4hours Water was added, the phases were separated and the aqueous layerwas extracted with CH₂Cl₂. The combined organic layers were dried overNa₂SO₄ and concentrated. The residue was swished in EtOAc to provide 22mg of the title compound as a pale yellow solid.

[0392]¹H NMR (acetone-d₆) δ 7.34 (1H, dd), 7.21 (2H, d), 7.14 (1H, dd),6.99 (d, 2H), 4.39-4.28 (1H, m), 4.05-3.97 (1H, m), 3.89-3.78 (1H, m),3.62 (3H, s), 2.85-2.71 (2H, m), 2.33-2.18 (m, 1H), 2.15-1.95 (2H, m).

[0393] Step 7:(+/−)-[1-Bromo-10-[(4-chlorophenyl)sulfanyl]-3-fluoro-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]aceticacid

[0394] To a solution of the ester of Step 6 (45 mg) in a THF/MeOH (3:1)mixture at r.t. was added 1N LiOH (aqueous solution). The reactionmixture was stirred at r.t. for 2 h and AcOH was added. The aqueouslayer was extracted with EtOAc and the combined organic layers weredried over Na₂SO₄ and concentrated. The residue was swished in EtOAc toprovide 20 mg of the title compound as a white solid.

[0395]¹H NMR (acetone-d₆) δ 8.56 (1H, br s), 7.24 (1H, dd), 7.15 (2H,d), 7.10 (1H, dd), 6.91 (2H, d), 4.32-4.26 (1H, m), 3.90-3.82 (2H, m),2.69-2.64 (1H, m), 2.48-2.39 (1H, m), 2.37-2.24 (1H, m), 2.17-2.01 (2H,m), 1.95-1.86 (1H, m).

[0396] MS (−APCI) m/z 468.1 (M−H)⁻.

EXAMPLE 9

[0397](+/−)-[10-[(4-chlorophenyl)sulfanyl]-1-methoxy-3-(methyl-sulfonyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-tl]aceticacid

[0398] Step 1: 2-Methoxy-4-(methylsulfanyl)benzaldehyde

[0399] To a vigorously stirred solution of 11.4 g of methyl 2methoxy-4-(methylsulfanyl)benzoate in 200 mL of THF cooled at −78° C.was added dropwise a solution of diisobutylaluminum hydride (72 mL, 1.5M in toluene). After stirring for 1.25 hours at −78° C., the reactionwas quenched with 5 mL of acetone followed by 150 mL of 1 N HCl. Themixture was extracted with 2×150 mL of ether and the extracts were driedover Na₂SO₄, filtered through a pad of silica gel and concentrated.

[0400] To a solution of 13.7 g of oxalyl chloride in 250 mL of CH₂Cl₂cooled at −78° C. was added slowly 16.9 g of DMSO. After stirring for 5minutes, a solution of the crude alcohol obtained above in 50 mL ofCH₂Cl₂ was added and the mixture was stirred for 30 minutes at −60° C.and then treated with 54 g of Et₃N. The mixture was warmed to roomtemperature and stirred for 10 minutes, quenched with 100 mL of 1N HCl.The product was extracted with 200 mL of CH₂Cl₂ and the extract wasdried over Na₂SO₄, concentrated., The residue was purified by silica gelflash chromatography eluted with 1:1 hexane/EtOAc to give 9 g of thetitle compound as yellow solid.

[0401]¹H NMR (acetone-d₆) δ 10.30 (1H, s), 7.64 (1H, d), 7.00 (1H, s),6.90 (1H, d), 3.99 (3H, s), 2.58 (3H, s).

[0402] Step 2:1-Methoxy-3-(methylsulfanyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-one

[0403] Starting from 2-methoxy-4-(methylsulfanyl)benzaldehyde, the titlecompound was synthesized following the procedures described in Steps 3-4of Example 7 and Steps 2-4 of Example 8.

[0404]¹H NMR (acetone-d₆) δ 7.12 (1H, s), 6.95 (1H, s), 6.50 (1H, s),4.28 (2H, t), 3.95(3H, s), 2.65 (2H, t), 2.57 (3H, s), 2.48 (2H, m).

[0405] Step 3:1-Methoxy-3-(methylsulfonyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-one

[0406] A solution of 0.2 g of the product obtained from Step 2, 1 mL ofH₂O₂ and 0.05 g of Na₂WO₄ (dihydrate) in 5 mL of EtOH was stirred for 1h at room temperature and 30 minutes at 50° C. The solution was cooledand concentrated. The residue was partitioned between 15 mL of brine and60 mL of EtOAc. The EtOAc layer was dried over Na₂SO₄ and concentrated.The crude product was swished from 1:1 hexane/EtOAc to give 0.18 g ofthe title compound as a white solid.

[0407]¹H NMR (acetone-d₆) δ 7.75 (1H, s), 7.22 (1H, s), 7.05 (1H, s),4.47 (2H, t), 4.06(3H, s), 3.15 (3H, s), 2.76 (2H, t), 2.48 (2H, m).

[0408] Step 4: E/Z-Ethyl2-[1-methoxy-3-(methylsulfonyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yliden]acetate

[0409] To a solution of 0.5 mL of triethyl phosphonoacetate in 3.5 mL ofDMF was added 0.1 g of NaH (60% in mineral oil). After stirring for 10minutes, 0.1 g of the product obtained in Step 3 was added and themixture was stirred for 30 minutes at room temperature and 1 hour at 45°C. The mixture was poured into 20 mL of saturated aqueous NH₄Cl andextracted with 2×20 mL of EtOAc. The residue was purified by silica gelflash chromatography eluted with 3:2 hexane/EtOAc to give 0.14 g of thetitle compound as yellow oil.

[0410]¹H NMR (acetone-d₆) δ 7.58 (1H, s), 7.00 (1H, s), 6.58 (1H, s),6.10 (1H, bt), 4.27 (2H, t), 4.10 (2H, q), 2.68-2.80 (4H, m).

[0411] Step 5: Ethyl2-[1-methoxy-3-(methylsulfonyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]acetate

[0412] Starting from the product obtained in Step 4, the title compoundwas synthesized following the procedures described in Step 7 of Example1.

[0413]¹H NMR (acetone-d₆) δ 7.57 (1H, s), 7.02 (1H, s), 6.42 (1H, s),4.32 (1H, m), 4.16 (2H, q), 4.02 (1H, m), 4.00 (3H, s), 3.45 (1H, m),3.08 (3H, s), 2.95 (1H, dd), 2.61 (1H, dd), 2.25 (1H, m), 2.13 (1H, m),2.05 (1H, m), 1.63 (1H, m).

[0414] Step 6:(+/−)-[10-[(4-Chlorophenyl)sulfanyl]-1-methoxy-3-(methylsulfonyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]aceticacid

[0415] Starting from the product obtained in Step 5, the title compoundwas synthesized following the procedures described in Step 9-10 ofExample 7.

[0416]¹H NMR (acetone-d₆) δ 7.69 (1H, s), 7.20 (2H, d), 7.08 (1H, s),7.04 (2H, d), 4.45 (1H, m), 4.08 (1H, m), 3.72 (1H, m), 3.77 (3H, s),3.10 (3H, s), 2.75-2.82 (2H, m), 2.27 (1H, m), 2.12 (1H, m), 2.05 (2H,m).

EXAMPLE 10

[0417](+/−)-[8-acetyl-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0418] Step 1: (+/−)-Methyl[8-acetyl-9-[(4-chlorophenyl)sulfanl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0419] A mixture of palladium (II) acetate (45 mg, 0.2 mmol) andtriphenyl arsine (122 mg, 0.4 mmol) in DMF (0.5 mL) was sonicated for 10minutes and then degassed. A solution of(+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 7, 235 mg, 0.5 mmol) in 2 mL of DMF and1-ethoxyvinyltri-n-butyltin (451 mg, 1.3 mmol) were added and themixture was degassed. The reaction mixture was stirred at 90° C. for 12hours and 1N HCl (4 mL) was added. The mixture was stirred at 90° C. for2 hours and extracted with EtOAc. The combined organic layers werewashed with 1N HCl, brine and water, dried over Na₂SO₄ and concentrated.The residue was purified by silica gel chromatography eluted with 20%EtOAc in Hexanes to provide 100 mg (70% pure) of the title compound as apale yellow oil used as such.

[0420] Step 2:(+/−)-[8-Acetyl-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0421] To a solution of the ester of Step 1 (100 mg) in a THF/MeOH (3:1)mixture at r.t. was added 1N LiOH (aqueous solution). The reactionmixture was stirred at r.t. for 2 h and AcOH was added. The aqueouslayer was extracted with EtOAc and the combined organic layers weredried over Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography eluted with EtOAc/Hexanes/AcOH (20:30:1) to provide55 mg of the title compound as a pale yellow solid.

[0422]¹H NMR (acetone-d₆) δ 7.35 (1H, dd), 7.21 (2H, d), 7.02-6.96 (311,m), 4.43-4.36 (1H, m), 4.27-4.21 (1H, m), 3.86-3.78 (1H, m), 3.17 (1H,dd), 3.08-2.99 (1H, m), 2.67 (1H, dd), 2.54-2.46 (1H, m), 2.38 (3H, s).MS (−APCI) m/z 416.0 (M−H)⁻.

EXAMPLE 11

[0423](+/−)-[9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(tri-fluoroacetyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0424] Step 1:(+/−)-[9-[(4-Chlorophenyl)sulfanyl]-6-fluoro-8-(trifluoroacetyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0425] To a solution of(+/−)-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid (Example 7, 250 mg, 0.6 mmol) in THF (8 mL) at −78° C. was added 3MMeMgBr (0.7 mmol) followed by the addition of sec-BuLi (0.8 mmol, 1.3Msolution). The reaction mixture was stirred at −78° C. for 5 minutes andmethyl trifluoroacetate (352 mg, 2.8 mmol) was added., The reactionmixture was warmed to r.t., stirred for 4 hours and saturated aqueousNH₄Cl was added. The phases were separated and the aqueous layer wasextracted with EtOAc. The combined organic layers were dried over Na₂SO₄and concentrated. The residue was purified by silica gel chromatographyeluted with EtOAc/Hexanes/AcOH (20:30:1) to provide 150 mg of the titlecompound as a white solid.

[0426]¹H NMR (acetone-d₆) δ 7.64 (1H, dd), 7.26-7.20 (3H, m), 6.97 (2H,d), 4.50-4.43 (1H, m), 4.36-4.30 (1H, m), 3.90-3.83 (1H, m), 3.18 (1H,dd), 3.10-3.02 (1H, m), 2.73 (1H, dd), 2.58-2.50 (1H, m). MS (−APCI) m/z470.1 (M−H)⁻.

EXAMPLE 12

[0427](+/−)-[9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0428] To a solution of(+/−)-[9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(trifluoroacetyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid (Example 11, 78 mg) in MeOH (5 mL) at r.t. was added 50 mg ofNaBH₄. The reaction mixture was stirred at r.t. for 3 hours and 1N HClwas slowly added The aqueous layer was extracted with EtOAc and thecombined organic layers were dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel chromatography eluted withEtOAc/Hexanes/AcOH (20:30:1) to provide 60 mg of the title compound as awhite solid.

[0429] (Mixture of diastereomers) ¹H NMR (acetone-d₆) δ 7.31-7.23 (8H,m), 7.05-7.03 (4H, m), 6.59-6.54 (1H, m), 6.47-6.43 (1H, m), 5.95-5.75(2H, br s), 4.42-4.36 (2H, m), 4.28-4.21 (2H, m), 3.88-3.77 (2H, m),3.29-3.24 (1H, m), 3.10-2.98 (3H, m), 2.74-2.60 (2H, m), 2.54-2.46 (2H,m).

EXAMPLE 13

[0430](+/−)-[9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(1-hydroxy-2-methylpropyl)-2,3dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid

[0431] To a solution of(+/−)-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid (Example 7, 100 mg, 0.22 mmol) in THF (4 mL) at −78° C. was added3M MeMgBr (0.26 mmol) followed by the addition of 1.3M sec-BuLi (0.31mmol). The reaction mixture was stirred at −78° C. for 20 minutes and anexcess of isobutyraldehyde was added. The reaction mixture was slowlywarmed to −20° C. over a 30 minute period and quenched with saturatedaqueous NH₄Cl. The phases were separated and the aqueous layer wasextracted with EtOAc. The combined organic layers were dried over Na₂SO₄and concentrated. The residue was purified by preparative HPLC using aZorbax column eluted with 10% iPrOH in Hexanes containing 0.2% of AcOHto provide 40 mg of the title compound as a white solid.

[0432] (Mixture of diastereomeres) ¹H NMR (acetone-d₆) δ 7.24 (4H, d),7.17-7.01 (8H, m), 5.59-5.54 (1H, m), 5.47-5.43 (1H, m), 4.37-4.30 (2H,m), 4.23-4.16 (2H, m), 4.05-3.95 (2H, m), 3.84-3.76 (2H, m), 3.25 (1H,dd), 3.10 (1H, dd), 3.05-2.97 (2H, m), 2.72-2.57 (2H, m), 2.52-2.43 (2H,m), 2.09-1.97 (2H, m), 0.97-0.90 (6H, m), 0.76 (6H, d). MS (−APCI) m/z446.2 (M−H)⁻.

EXAMPLE 14

[0433](+/−)-[9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(1-hydroxy-ethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0434] To a solution of(+/−)-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid (Example 7, 100 mg, 0.22 mmol) in THF (4 mL) at −78° C. was added3M MeMgBr (0.26 mmol) followed by the addition of 1.3M sec-BuLi (0.31mmol). The reaction mixture was stirred at −78° C. for 5 minutes and anexcess of acetaldehyde was added. The reaction was stirred at −78° C.for 30 minutes and quenched with saturated aqueous NH₄Cl. The phaseswere separated and the aqueous layer was extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel chromatography eluted withEtOAc/Hexanes/AcOH (20:30:1) to provide 65 mg of the title compound as awhite solid.

[0435] (Mixture of diastereomers) ¹H NMR (acetone-d₆) δ 7.26-7.19 (6H,m), 7.08-7.01 (6H, m), 5.91 (1H, q), 5.80 (1H, q), 4.37-4.31 (2H, m),4.22-4.15 (2H, m), 3.84-3.77 (2H, m), 3.22 (1H, dd), 3.13 (1H, dd),3.04-2.96 (2H, m), 2.71-2.58 (2H, m), 2.52-2.42 (2H, m), 1.35 (3H, d),1.30 (3H, d).

[0436] MS (−APCI) m/z 418.2 (M−H)⁻.

EXAMPLE 15

[0437](+/−)-[9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(1-methoxy-ethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0438] Step 1: (+/−)-Methyl[9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(1-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0439](+/−)-[9-[(4-Chlorophenyl)sulfanyl]-6-fluoro-8-(1-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid (Example 14, 100 mg) was esterified in Et₂O by addition of anexcess of CH₂N₂. After removal of the solvents, the title ester wasobtained quantitatively as a pale yellow solid and used as such.

[0440] Step 2: (+/−)-Methyl[9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(1-methoxyethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0441] To a solution of the alcohol of Step 1 (105 mg, 0.25 mmol) in DMF(5 mL) at 0° C. was added NaH (11 mg, 0.3 mmol). The reaction mixturewas stirred at 0° C. for 20 minutes and MeI (51 mg, 0.4 mmol) was added.The reaction was stirred at 0° C. for 30 minutes and quenched withsaturated aqueous NH₄Cl and extracted with EtOAc. The combined organiclayers were washed with brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel chromatography eluted with 30% EtOAcin Hexanes to provide 90 mg of the title compound as a white solid.

[0442] (Mixture of diastereomers) ¹H NMR (acetone-d₆) δ 7.29-7.26 (4H,m), 7.13-7.04 (6H, m), 6.98 (2H, dd), 5.48-5.44 (1H, m), 5.30-5.26 (1H,m), 4.38-4.32 (2H, m), 4.24-4.18 (2H, m), 3.87-3.83 (2H, m), 3.63 (3H,s), 3.59 (3H, s), 3.23-2.95 (4H, m), 2.96 (3H, s), 2.90 (3H, s),2.75-2.68 (2H, m), 2.50-2.43 (2H, m), 1.30 (3H, d), 1.21 (3H, d). MS(+APCI) m/z 416.1 (M-OMe)⁺.

[0443] Step 3:(+/−)-[9-[(4-Chlorophenyl)sulfanyl]-6-fluoro-8-(1-methoxyethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0444] The ester of Step 2 (80 mg) was hydrolyzed using the proceduredescribed in Example 10, Step 2 to provide 70 mg of the title acid as awhite foam.

[0445] Mixture of diastereomer: ¹H NMR (methanol-d₄) δ 7.22-7.19 (4H,m), 7.04-6.91 (8H, m), 5.57-5.52 (1H, m), 5.43-5.39 (1H, m), 4.27-4.23(2H, m), 4.14-4.08 (2H, m), 3.85-3.80 (2H, m), 3.19-2.88 (4H, m), 2.97(3H, s), 2.92 (3H, s), 2.46-2.40 (2H, m), 2.34-2.24 (2H, m), 1.30 (3H,d), 1.25 (3H, d).

[0446] MS (−APCI) m/z 432.3 (M−H)⁻.

EXAMPLE 15A

[0447][9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(1-methoxy-ethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid (as a pair of diastereomers)

[0448] Step 1:[9-[(4-Chlorophenyl)sulfanyl]-6-fluoro-8-(1-hydroxyethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0449] The title compound was prepared following the proceduresdescribed in Example 14 staring from(+)-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid (Example 7A).

[0450] Step 2:[9-[(4-Chlorophenyl)sulfanyl]-6-fluoro-8-(1-methoxyethyl)-2,3-dihydro-1h-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0451] Starting from the product of Step 1 and following the methodsdescribed in Steps 1-3 of Example 15, two diastereomers were obtained,which were resolved by preparative HPLC on a chiralpak A/D preparativecolumn eluted with a mixture of 5% iPrOH in hexanes+0.2% AcOH. Bothisomer A and isomer B were obtained as a white solid with diastereomericexcess>95%.

[0452] Isomer A (less polar isomer): ¹H NMR (acetone-d₆) δ 7.27 (2H, d),7.13 (1H, dd), 7.08 (2H, d), 6.97 (1H, dd), 5.29 (1H, q), 4.39-4.33 (1H,m), 4.24-4.18 (1H, m), 3.89-3.82 (1H, m), 3.14 (1H, dd), 3.05-2.95 (1H,m), 2.89 (3H, s), 2.67 (1H, dd), 2.52-2.46 (1H, m), 1.29 (3H, d), MS(−APCI) m/z 432.3 (M−H)⁻. [o]D=+151°, c=0.1 of sodium salt in acetone.

[0453] Isomer B (more polar isomer): ¹H NMR (acetone-d₆) δ 7.27 (2H, d),7.13 (1H, dd), 7.08 (2H, d), 6.97 (1H, dd), 5.49-5.44 (1H, m), 4.38-4.33(1H, m), 4.24-4.18 (1H, m), 3.87-3.81 (1H, m), 3.23 (1H, dd), 3.05-2.96(1H, m), 2.95 (3H, s), 2.70 (1H, dd), 2.52-2.45 (1H, m), 1.22 (3H, d),MS (−APCI) m/z 432.3 (M−H)⁻. [α]_(D)−=5°, c=0.1 of sodium salt inacetone.

EXAMPLE 16

[0454](+/−)-[8-acetyl-6-fluoro-9-(phenylsulfanyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0455] Step 1: (+/−)-Methyl(8-acetyl-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[0456] A mixture of tris(dibenzyllideneacetone)dipalladium (281 mg, 0.3mmol) and triphenyl arsine (367 mg, 1.2 mmol) in DMF (4 mL) wassonicated for 10 minutes and then degassed. A solution of (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8, 200 mg, 0.6 mmol) in 3 mL of DMF and1-ethoxyvinyltri-n-butyltin (650 mg, 1.8 mmol) were added and themixture was degassed. The reaction mixture was stirred at 90° C. for 12hours and 1N HCl (4 mL) was added. The mixture was stirred at 90° C. for12 hours and extracted with EtOAc. The combined organic layers werewashed with 1N HCl, brine and water, dried over Na₂SO₄ and concentrated.The residue was purified by silica gel chromatography eluted with 20%EtOAc in hexanes to provide the title compound (70% pure) as a paleyellow oil used as such.

[0457] Step 2: (+/−)-Methyl[8-acetyl-6-fluoro-9-(phenylsulfanyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0458] Starting from diphenyl disulphide (93 mg, 0.43 mmol) and theester of Step 1 (50 mg, 0.17 mmol) the title compound was synthesized asdescribed Step 9, Example 7 as pale yellow foam.

[0459]¹H NMR (acetone-d₆) δ 7.34 (1H, dd), 7.19 (2H, t), 7.08 (1H, t),6.98 (2H, d), 6.93 (1H, dd), 4.42-4.37 (1H, m), 4.28-4.23 (1H, m),3.87-3.80 (1H, m), 3.61 (3H, s), 3.17 (1H, dd), 3.05-2.98 (1H, m), 2.69(1H, dd), 2.49-2.44 (1H, m), 2.32 (3H, s).

[0460] Step 3:(+/−)-[8-Acetyl-6-fluoro-9-(phenylsulfanyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0461] The ester of Step 2 (25 mg) was hydrolyzed using the proceduredescribed in Example 10, Step 2 to provide the title compound as a paleyellow foam.

[0462]¹H NMR (acetone-d₆) δ 7.34 (1H, dd), 7.19 (2H, t), 7.07 (1H, t),7.0 (2H, d), 6.93 (1H, dd), 4.43-4.37 (1H, m), 4.28-4.22 (1H, m),3.83-3.77 (1H, m), 3.22 (1H, dd), 3.06-2.99 (1H, m), 2.65 (1H, dd),2.53-2.46 (1H, m), 2.32 (3H, s), MS (−APCI) m/z 382.3 (M−H)⁻.

EXAMPLE 17

[0463](+/−)-[8-acetyl-9-[(3,4-dichlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0464] Step 1: (+/−)-Methyl[8-acetyl-9-[(3,4-dichlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0465] Starting from bis(3,4-dichlorophenyl) disulphide (153 mg, 0.43mmol) and (+/−)-methyl(8-acetyl-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 16, Step 1, 50 mg, 0.17 mmol) the title compound wassynthesized as described in Step 9 of Example 7 as a pale yellow foam.

[0466]¹H NMR (acetone-d₆) δ 7.37-7.34 (2H, m), 7.10 (1H, d), 7.02 (1H,dd), 6.93 (1H, dd), 4.41-4.35 (1H, m), 4.26-4.21 (1H, m), 3.86-3.80 (1H,m), 3.58 (3H, m), 3.09 (1H, dd), 3.02-2.94 (1H, m), 2.71 (1H, dd),2.50-2.43 (1H, m), 2.39 (3H, s).

[0467] Step 2:(+/−)-[8-Acetyl-9-[(3,4-dichlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0468] The ester of Step 1 (28 mg) was hydrolyzed using the proceduredescribed in Example 10, Step 2 to provide the title compound as a paleyellow foam.

[0469]¹H NMR (acetone-d₆) δ 7.37 (2H, m), 7.15 (1H, d), 7.04 (1H, dd),6.97 (1H, dd), 4.44-4.38 (1H, m), 4.29-4.23 (1H, m), 3.86-3.81 (1H, m),3.16 (1H, dd), 3.05-2.99 (1H, m), 2.70 (1H, dd), 2.55-2.49 (1H, m), 2.43(3H, s), MS (−APCI) ra/z 450.1 (M−H)⁻.

EXAMPLE 18

[0470](+/−)-[9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(2,2,2-trifluoro-1-methoxyethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0471] Step 1: (+/−)-Methyl[9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(2,2,2-trifluoro-1-methoxyethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0472] To a solution of(+/−)-[9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(2,2,2-trifluoro-1-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid (Example 12, 27 mg, 0.07 mmol) in DMF (4 mL) at 0° C. was added NaH(24 mg, 0.6 mmol, 60% in oil). The reaction mixture was stirred at 0° C.for 15 minutes and methyl iodide (52 mg, 0.36 mmol) was added. Thereaction mixture was stirred for 15 minutes and quenched with saturatedaqueous NH₄Cl and extracted with EtOAc. The combined organic layers weredried over Na₂SO₄, concentrated and used as such.

[0473] Step 2:(+/−)-[9-[(4-Chlorophenyl)sulfanyl]-6-fluoro-8-(2,2,2-trifluoro-1-methoxyethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0474] The ester of Step 1 (30 mg) was hydrolyzed using the proceduredescribed in Example 10, Step 2 to provide the title compound as a whitesolid.

[0475] (Mixture of diastereomers) ¹H NMR (acetone-d₆) δ 7.39-7.34 (2H,m), 7.31-7.27 (4H, m), 7.12-7.0 (6H, m), 6.12-6.07 (1H, m), 5.96-5.91(1H, m), 4.45-4.38 (2H, m), 4.30-4.24 (m, 2H), 3.93-3.85 (2H, m), 3.27(1H, dd), 3.13 (1H, dd), 3.09-3.01 (2H, m), 3.00 (3H, s), 2.93 (3H, s),2.80-2.69 (2H, m), 2.56-2.49 (2H, m), MS (−APCI) m/z 486.3(M−H)⁻.

EXAMPLE 19

[0476][9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(1-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0477] To a solution of(+)-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid (Example 7A, 700 mg, 1.5 mmol) in THF (15 mL) at −78° C. was added3M MeMgBr in THF (1.9 mmol) followed by the addition of 1.6M nBuLi inhexane (3.1 mmol). The reaction mixture was stirred at −78° C. for 2minutes and an excess of propionaldehyde was added. The reaction mixturewas stirred at −78° C. for 15 minutes, warmed to r.t and quenched withsaturated aqueous NH₄Cl The phases were separated and the aqueous layerwas extracted with EtOAc. The combined organic layers were dried overNa₂SO₄ and concentrated. The residue was purified by silica gelchromatography eluted with EtOAc/hexanes/AcOH (20:30:1) to provide thetitle compound as a white solid.

[0478] (Mixture of two diastereomeres) ¹H NMR (acetone-d₆) δ 7.25-7.15(6H, m), 7.08-7.03 (6H, m), 5.67-5.63 (1H, m), 5.56-5.52 (1H, m),4.37-4.31 (2H, m), 4.23-4.16 (2H, m), 4.85-4.79 (2H, m), 3.22 (1H, dd),3.12 (1H, m), 3.05-2.95 (2H, m), 2.70-2.60 (2H, m), 2.51-2.45 (2H, m),1.78-1.65 (2H, m), 1.53-1.47 (2H, m), 0.93-0.85 (6H, m), MS (−APCI) m/z432.3 (M−H)⁻.

EXAMPLE 20

[0479][9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(1-methoxypropyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0480] Step 1:Methyl[9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(1-methoxypropyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0481] To a solution of([9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(1-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid (Example 19, mixture of two diastereomers, 525 mg, 1.2 mmol) in DMF(20 mL) at 0° C. was added NaH (480 mg, 12 mmol). The reaction mixturewas stirred at 0° C. for 15 minutes and methyl iodide (1.02 g, 7.2 mmol)was added. The reaction mixture was stirred for 15 minutes, quenchedwith saturated aqueous NH₄Cl and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel chromatography eluted with EtOAc/hexanes (30:70)to provide the title compound as a yellow oil.

[0482] (Mixture of two diastereomeres) ¹H NMR (acetone-d₆) δ 7.28-7.23(4H, m), 7.11-7.01 (6H, m), 6.91 (2H, dd), 5.21-5.18 (1H, m), 5.03-5.0(1H, m), 4.354.29 (2H, m), 4.21-4.16 (21H, m), 3.86-3.80 (2H, m), 3.61(3H, s), 3.56 (3H, s), 3.16 (1H, dd), 3.07 (1H, dd), 3.01-2.93 (2H, m),2.92 (3H, s), 2.85 (3H, s), 2.72-2.66 (2H, m), 2.47-2.41 (2H, m),1.67-1.62 (1H, m), 1.55-1.46 (3H, m), 0.85 (3H, t), 0.77 (3H, t).

[0483] Step 2:[9-[(4-Chlorophenyl)sulfanyl]-6-fluoro-8-(1-methoxypropyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0484] The ester of Step 1 (540 mg) was hydrolyzed using the proceduredescribed in Example 10, Step 2 to provide the title compound (mixtureof 2 diastereomers) as a yellow syrup. The two diastereomers wereseparated by preparative HPLC on a chiralpak A/D preparative columneluted with a mixture of 5% iPrOH in hexanes+0.2% AcOH, to give isomer A(less polar isomer) and isomer B (more polar isomer) as a white foam.

[0485] Isomer A: ¹H NMR (acetone-d₆) δ 7.28 (2H, d), 7.13 (1H, dd), 7.08(2H, d), 6.94 (1H, dd), 5.07-5.04 (1H, m), 4.38-4.33 (1H, m), 4.24-4.18(1H, m), 3.88-3.82 (1H, m), 3.15 (1H, dd), 3.06-2.98 (1H, m), 2.88 (3H,s), 2.68 (1H, dd), 2.53-2.45 (1H, m), 1.70-1.65 (1H, m), 1.58-1.51 (1H,m), 0.88 (3H, t). [α]_(D)=+1480, c=0.1 of sodium salt in MeOH.

[0486] Isomer B: ¹H NMR (acetone-d₆) δ 7.24 (2H, d), 7.10 (1H, dd), 7.05(2H, d), 6.91. (1H, dd), 5.21-5.18 (1H, m), 4.35-4.30 (1H, m), 4.21-4.16(1H, m), 3.84-3.80 (1H, m), 3.20 (1H, dd), 3.02-2.95 (1H, m), 2.92 (3H,s), 2.67 (1H, dd), 2.49-2.43 (1H, m), 1.55-1.47 (2H, m), 0.78 (3H, t).[α]_(D)=−5, c=0.1 of sodium salt in MeOH.

EXAMPLE 21

[0487][9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-[1-(methyl-sulfanyl)ethyl]-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0488] Methanethiol was bubbled into a solution of[9-[(4-chlorophenyl)-sulfanyl]-6-fluoro-8-(1-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid (Example 15A, Step 1, 48 mg, 0.1 mmol) in5 mL of dichloro'methane at 0° C. and zinc iodide (5 mg, 0.015 mmol) wasadded. The reaction mixture was stirred at 0° C. for 15 minutes andquenched with saturated aqueous NH₄Cl and extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄ and concentrated. Theresidue was purified by preparative HPLC with a C18 Zorbax column usinga mixture of 5% iPrOH in hexanes+0.2% AcOH as eluant to provide thetitle compound as a white solid foam.

[0489] Mixture of diastereomer: ¹H NMR (acetone-d₆) δ 7.28-7.25 (4H, m),7.18-7.07 (8H, m), 5.34-5.28 (1H, m), 5.24-5.22 (1H, m), 4.38-4.31 (2H,m), 4.24-4.17 (2H, m), 3.88-3.81 (2H, m), 3.21-3.15 (2H, m), 3.06-2.97(2H, m), 2.73-2.62 (2H, m), 2.52-2.43 (2H, m), 1.75 (3H, s), 1.67 (3H,s), 1.40 (3H, d), 1.34 (3H, d), MS (−APCI) m/z 448.1 (M−H)⁻.

EXAMPLE 22

[0490](+/−)-[9-[(4-chlorophenyl)sulfanyl]-6-methoxy-8-(methyl-sulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0491] Step 1: 2-Bromo-4-methoxybenzaldehyde

[0492] To a solution of 2-bromo-4-fluorobenzaldehyde (50 g, 246 mmol),in MeOH (500 mL) in a 15° C. water bath was added a 25% solution ofNaOMe/MeOH (88 mL). The mixture was stirred at r.t. for 1 hour followedby 2 hours at reflux. The solid was filtered and the filtrate wasconcentrated to dryness to give a second crop of solid. Both crops weretaken up in CH₂Cl₂/H₂O. After washing with H₂O, the organic phase wasdried (MgSO₄), filtered, and evaporated to give an off-white solid (52.2g).

[0493] Step 2:Methyl(2Z)-2-azido-3-(2-bromo-4-methoxyphenyl)-2-propenoate

[0494] A solution of the aldehyde from Step 1 (25 g, 116 mmol) in MeOH(200 mL) and THF (20 mL) was prepared and methyl azidoacetate (53 g)Synth. Commun. 675 (1991) was added. The resulting solution was added,over 30 minutes to a −10° C. (internal probe) solution of 25%(w/w) NaOMein MeOH (100 mL). The mixture was then stirred at 0° C. for 3 hours,followed by overnight in an ice bath in the cold room. The suspensionwas then poured onto a mixture of ice water and NH₄Cl, and the productwas extracted with EtOAc. The organic phase was washed with saturatedNH₄Cl and brine, dried (Na₂SO₄), filtered and evaporated. The crudematerial was dissolved in CH₂Cl₂ and filtered through a plug of silicagel. After evaporation, the solvent was stirred with 1:5 Et₂O/hexane togive, after filtration, 25.3 g of a yellow solid.

[0495] Step 3: Methyl 4-bromo-6-methoxy-1H-indole-2-carboxylate

[0496] To refluxing xylenes (10 mL) was added slowly a solution of theazido compound of Step 2 (1.0 g, 3.2 mmol) in xylenes (10 mL). When theaddition was completed, heating was continued for a further 5 minutes,at which point the mixture was cooled to RT and finally to 0° C. for 30minutes. The product was collected by filtration, washing with hexane.An off-white solid (0.8 g) was obtained.

[0497] Step 4:8-Bromo-6-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one

[0498] To a solution of the ester from Step 3 (0.5 g, 1.76 mmol) intoluene (7 mL) and THF (1 mL) at RT was added 1M potassium t-butoxide(1.76 mL, 1.76 mmol). After 15 minutes, methyl acrylate (0.32 mL, 3.5mmol) was added, and the mixture was brought to reflux for 1.5 hours.The reaction was quenched by the addition of saturated NH₄Cl solution,and the product was extracted with EtOAc/THF. The organic layer waswashed with H₂O and brine, dried (MgSO₄), filtered, and evaporated. Theintermediate was suspended in EtOH (10 mL), and concentrated HCl (2 mL)was added. After heating to reflux for 2 hours, the mixture was cooledand diluted with H₂O (30 mL). The product was extracted with CH₂Cl₂ andthe organic phase was washed with H₂O before drying (MgSO₄). Followingfiltration and removal of solvent under vacuum, the product was stirredwith 1:2 EtOAc:hexane to give a tan-coloured solid (0.4 g).

[0499] Step 5:Methyl(8-bromo-6-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[0500] A mixture of the ketone from Step 4 (0.4 g, 1.43 mmol), methylbromoacetate (0.7 mL, 7.1 mmol), and Zn/Cu couple (0.46 g, 7.1 mmol) inTHF (6 mL) was suspended in an ultrasound bath for 45 minutes. SaturatedNH₄Cl solution and EtOAc were then added, and the suspension wasfiltered through abed of Celite. The organic phase was washed with H₂Oand brine, dried (MgSO₄), filtered and evaporated. The crude materialwas purified by flash chromatography (1:1 EtOAc/hexane) and theresulting intermediate was dissolved in CH₃CN (10 mL). This solution wasthen added to a stirring mixture of TMSCl (0.8 mL, 6.4 mmol) and NaI(0.95 g, 6.4 mmol) in CH₃CN (4 mL) in a RT H₂O bath. Saturated NaHCO₃solution and sodium sulfite were added, and the product was extractedwith EtOAc. The organic layer was washed with H₂O and brine, dried(MgSO₄), filtered, and evaporated to give a pale yellow solid (0.40 g).

[0501] Step 6:Methyl{8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-methoxy-2.3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate

[0502] To a solution of bis(4-chlorophenyl)disulfide (0.59 g, 2.07 mmol)in dichloroethane (10 mL) at r.t. was added SO₂Cl₂ (0.12 mL, 1.55 mmol).After stirring at r.t. for 25 minutes 80% of this yellow solution wasthen added to a solution of the indole from Step 5 (0.35 g, 1.03 mmol)in DMF (10 mL). Saturated NaHCO₃ solution was then added, and theproduct was extracted with 1:1 Et₂O/EtOAc. The organic phase was washedwith H₂O and brine, dried (MgSO₄), filtered, and evaporated. The crudeproduct was purified by flash chromatography, eluting with 1:5EtOAc:hexane (yield=0.37 g).

[0503] Step 7:Methyl[9-[(4-chlorophenyl)sulfanyl]-6-methoxy-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0504] A degassed suspension of the product from Step 6 (0.15 g, 0.32mmol) NaSO₂Me (0.30 g, 1.6 mmol), and CuI (0.16 g, 1.6 mmol) in NMP (4mL) was stirred overnight at 130° C. EtOAc was then added, and themixture was filtered through a pad of silica gel. The filtrate waswashed with H₂O and brine, dried (MgSO₄), filtered, and evaporated. Theresidue was purified by flash chromatography, eluting with 1:2 and 1:1EtOAc:hexane to give a tan coloured solid (23 mg).

[0505] Step 8:[9-[(4-chlorophenyl)sulfanyl]-6-methoxy-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid

[0506] To a solution of the ester from Step 7 (23 mg, 0.048 mmol) in THF(3 mL) and MeOH (1 mL) at RT was added 1M LiOH (0.24 mL, 0.24 mmol).After stirring at r.t. for 4.5 hours, HOAc (10 drops) was added and thesolvent was evaporated. The residue was taken up in EtOAc/H₂O and theorganic phase was washed with brine, dried (MgSO₄), and filtered. Uponremoval of the solvent, the resulting solid was stirred with 1:5EtOAc:hexane to give a beige solid (20 mg).

[0507]¹H NMR (acetone d₆) δ 2.43-2.52 (m 1H), 2.59-2.68 (m, 1H),2.96-3.05 (m, 1H), 3.13-3.21 (m, 1H), 3.29 (s, 3H), 3.67-3.75 (m, 1H),3.95 (s, 3H), 4.25-4.32 (m, 1H), 4.40-4.47 (m, 1H), 7.00-7.05 (m, 2H),7.18-7.23 (m, 2H), 7.40-7.43 (m, 11), 7.50-7.53 (m, 1H), 10.80 (bs, 1H).

EXAMPLE 23

[0508](+/−)-[6-(benzyloxy)-9-[(4-chlorophenyl)sulfanyl]-8-(methyl-sulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0509] Step 1:Methyl[6-methoxy-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0510] In the same manner as Example 22 Step 7, the title compound wasprepared from the bromide of Example 22 Step 5.

[0511] Step 2:Methyl[6-hydroxy-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]-indol-1-yl]acetate

[0512] To a solution of the methyl ether from Step 1 (0.35 g, 1.03 mmol)in CH₂Cl₂ (5 mL) at 0° C. was added 1M BBr₃/CH₂Cl₂ (5.2 mL, 5.2 mmol)over a period of 55 minutes. The dark gummy suspension was then broughtto RT for 2.5 hours. MeOH (≈5 mL) was then added at −78° C. followed bysaturated NaHCO₃ solution. The cold bath was removed and the mixture wasstirred for 30 minutes. The product was then extracted with CH₂Cl₂ andthe organic phase was washed with H₂O. After drying (MgSO₄), filtering,and evaporating, the residue was purified by flash chromatography (1:2,1:1 EtOAc:hexane) to give a light brown solid (0.19 g).

[0513] Step 3:Methyl[6-(benzyloxy)-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0514] To a solution of the alcohol from Step 2 (0.19 g, 0.59 mmol) andbenzyl bromide (0.10 mL, 0.88 mmol) in DMF (4 mL) at 0° C. was addedCs₂CO₃ (0.29 g, 0.88 mmol). The mixture was stirred at RT for 1 hour,and then saturated NH₄Cl solution and H₂O were added. The product wasextracted with 1:1 EtOAc:Et₂O and the organic layer was washed with H₂Oand brine. After drying (MgSO₄), filtering, and removal of solvent, thecrude product was purified by flash chromatography (1:2 EtOAc:hexane) togive a tan coloured foam (0.23 g).

[0515] Step 4:Methyl[6-(benzyloxy)-9-[(4-chlorophenyl)sulfanyl]-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a}indol-1-yl]acetate

[0516] In the same manner as in Example 22 Step 6, the title compoundwas prepared from the benzyl ether of Step 3.

[0517] Step 5:[6-(benzyloxy)-9-[(4-chlorophenyl)sulfanyl]-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0518] In the same manner as in Example 22 Step 8, the title compoundwas prepared from the ester of Step 4.

[0519]¹H NMR (acetone d₆) δ 2.41-2.49 (m, 1H), 2.58-2.66 (m, 1H),2.92-3.00 (m, 1H), 3.10-3.17 (m, 1H), 3.27 (s, 3H), 3.65-3.71 (m, 1H),4.21-4.28 (m, 1H), 4.36-4.43 (m, 1H), 5.25 (s, 2H), 6.97-7.02 (m, 2H),7.14-7.20 (m, 2H), 7.31-7.36 (m, 1H), 7.37-7.45 (m, 2H), 7.47-7.50 (m,1H), 7.50-7.55 (m, 2H), 7.55-7.60 (m, 1H).

EXAMPLE 24

[0520](+/−)-[9-[4-Chlorophenyl)thio]-8-(methylsulfonyl)-6-methylthio)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid.

[0521] Step 1: 2-bromo-4-(methylthio)benzaldehyde

[0522] To 2-bromo-4-fluorobenzaldehyde (150 mg, 0.74 mmol) in methanol(2 mL) was added sodium thiomethoxide (80 mg, 1.1 mmol). The reactionmixture was heated to 50° C. for 1 hour. After cooling, the mixture wasquenched with saturated aqueous NH₄Cl and extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄, concentrated, and usedas such.

[0523] Step 2:(+/−)-[9-[(4-chlorophenyl)thio]-8-(methylsulfonyl)-6-methylthio)-2,3-dihydro-1H-pyrrolo[1-2-a]indol-1-yl]aceticacid

[0524] The procedures of Example 22, Steps 2-8 were followed using thecompound of Step 1 in place of 2-bromo-4-methoxybenzaldehyde to give thetitle compound.

[0525]¹H NMR (acetone d₆) δ 2.48 (m, 1H), 2.58 (s, 3H), 2.68(m, 1H),3.00(m, 1H), 3.18(m, 1H), 3.29(m, 3H), 3.70(m, 1H), 4.33 (m, 11),4.48(m, 1H), 7.02 (d, 2H), 7.18(d, 2H), 7.50 (m, 2H).

EXAMPLE 25

[0526](+/−)-[9-[(4-Chlorophenyl)thio]-8-isopropyl-6-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0527] Step 1:Methyl[8-bromo-6-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0528] To methyl[8-bromo-6-(methylthio)-2,3-dihydro-1H-pyrrolo(1,2-a]indol-1-yl]acetate(prepared according to the procedure of Example 22, Step 5, 500 mg, 1.48mmol) in MeOH (25 mL) was added Na₂WO₄ (260 mg, 0.79 mmol) followed byH₂O₂ 30% (1.6 mL) slowly. After 5 minutes the reaction was quenched byadding H₂O and extracted with EtOAc. The organic layer was dried overNa₂SO₄, filtered and evaporated. The residue was strirred with hexaneand EtOAc to give, after fitration, the title compound (300 mg).

[0529] Step 2:Methyl[8-isopropenyl-6-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0530] Alpha-bromopropene (514 μL, 5.2 mmol) was added portionwise, morder to maintain 55° C. exotherm, to Mg (126 mg, 5.2 mmol) (in THF 4mL) and a trace of iodine. The mixture was heated and stirred for 30minutes. Dried ZnBr₂ (1.16 g, 5.2 mmol) in THF (4 mL) was added and themixture was heated at 55° C. for 1 hour. The reaction mixture was cooledto room temperature, and Pd (dppf) CH₂Cl₂ (19 mg) was added followed byCuI (7 mg) after a further 5 minutes. The product of Step 1 (200 mg,0.52 mmol) in 3 ml THF was then added. The reaction mixture was heatedto 75° C. for 15 minutes. The reaction was quenched with saturatedaqueous NH₄Cl and extracted with EtOAc. The combined organic layers weredried over Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography to give the title compound (130 mg).

[0531] Step 3:Methyl[8-isopropyl-6-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[0532] To the product of Step 2 (130 mg, 0.39 mmol) in EtOH (3 mL) wasadded Pd/C 10% (40 mg). The mixture was hydrogenated with a Parrhydrogenator at 50 psi for 45 minutes, filtered on a pad of celite, andthe filtrate evaporated to dryness and used as such in the next step.

[0533] Step 4:Methyl[9-[(4-chlorophenyl)thio]-8-isopropyl-6-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0534] To 4,4′-dichlorodiphenyl disulfide (120 mg, 0.42 mmol) in1,2-dichloroethane (4 ml) was added SO₂Cl₂ (25 μl, 0.31 mmol). Thereaction mixture was stirred 25 minutes at r.t. Then, this yellowsolution was added to the product of Step 3 (140 mg, 0.42 mmol) in DMF(4 ml) at r.t. The reaction mixture was stirred for 1 hour and wasquenched with saturated NaHCO₃ and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel chromatography to give the title compound (140mg).

[0535] Step 5:[9-[(4-chlorophenyl)thio]-8-isopropyl-6-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0536] To a solution of the ester of Step 4 (140 mg) in THF/MeOH (3/1)mixture at r.t. was added 1 M LiOH (aqueous solution). The reactionmixture was stirred at r.t. for 2 hours and AcOH was added and thesolvent was evaporated. The residue was taken up in EtOAc/H₂O and theorganic phase was washed with brine, dried (MgSO₄), filtered andevaporated. The residue was purified by silica gel chromatographyeluting with 1% AcOH in EtOAc to give 100 mg of the title compound.

[0537]¹H NMR (acetone d₆) δ 1.22(m, 6H), 2.55(m, 1H), 2.78(m, 1H), 3.05(m, 1H), 3.22(m, 1H), 3.92 (m, 1H), 4.32 (m, 1H), 4.40 (m, 1H), 4.52(s,1H), 7.08(d, 2H), 7.25 (s, 2H), 7.60 (s, 1H), 7.87(s, 1H).

EXAMPLE 26

[0538](+/−)-[9-[(4-chlorophenyl)thio]-6-isopropoxy-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0539] Step 1:Methyl[6-isopropoxy-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0540] To methyl[6-hydroxy-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 23, Step 2, 130 mg, 0.4 mmol) in DMF (1.5 mL) at r.t. was added2-iodopropane (300 μL, 3 mmol) and Cs₂CO₃ (300 mg, 0.92 mmol). Thereaction mixture was stirred for 15 minutes, and was then quenched withsaturated aqueous NH₄Cl and extracted with EtOAc. The combined organiclayers were dried over NaSO₄ and concentrated. The residue was purifiedby silica gel chromatography to give the title compound (100 mg).

[0541] Step 2:Methyl[9-[(4-chlorophenyl)thio]-6-isopropoxy-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0542] The procedure of Example 25, Step 4 was followed using thecompound of Step 1 (80 mg, 0.23 mmol) in DMF (2 mL) to give the titlecompound (70 mg).

[0543] Step 3:(+/−)-[9-[(4-chlorophenyl)thio]-6-isopropoxy-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0544] To a solution of the ester of Step 2 (70 mg) in THF/MeOH (3:1)mixture at r.t. was added 1 M LiOH aqueous solution (1 mL). The reactionmixture was stirred at r.t. for 1 hour. Then AcOH was added. The aqueouslayer was extracted with EtOAC and the combined organic layers weredried over Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography, eluting with 1% AcOH in EtOAc to give 60 mg of thetitle compound.

[0545]¹H NMR (acetone d₆) δ 1.34 (m, 6H), 2.45 (m, 1H), 2.60 (m, 1H),2.98(m, 1H), 3.12(s, 1H), 3.28(m, 3H), 3.70 (s, 1H), 4.25(m, 1H),4.40(m, 1H), 4.72(m, 1H), 7.00 (d, 2H), 7.20(d, 2H), 7.38(s, 1H),7.50(s, 1H), 10.70 (bs, 1H).

EXAMPLE 27

[0546](+/−)-{6-(benzyloxy-9-[(4-chlorophenyl)thio]-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-yl]aceticacid

[0547] Step 1:Methyl(8-isopropenyl-6-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[0548] To Mg (143 mg, 5.8 mmol) in THF (4 mL) with trace of 12 was addedα-bromopropene (583 μL) in order to maintain a 60° C. exotherm. After 30minutes, a solution of ZnBr₂ (1.31 g, 5.8 mmol) in THF (4 mL) was added.The reaction mixture was heated at 55° C. for 1 hour, cooled to r.t. and(Pd (dppf) CH₂Cl₂ (50 mg) was added followed by CuI (18.5 mg). After 5minutes a solution of methyl(8-bromo-6-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 22, Step 5, 200 mg, 0.59 mmol) in THF (7 mL) was added and themixture was refluxed for 1 hour, cooled, quenched with saturated aqueousNH₄Cl and extracted with EtOAc. The combined organic layers were driedover Na₂SO₄ and concentrated. The residue was purified by silica gelchromatography to give the title compound (50 mg).

[0549] Step 2:Methyl(8-isopropyl-6-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0550] To the compound of Step 1 (200 mg, 0.67 mmol) in EtOH (20 mL) wasadded Pd/C 10% (100 mg). The mixture was hydrogenated with a Parrhydrogenator at 50 psi for 45 minutes the filtered on a pad of celite.The filtrate was evaporated to dryness and used as such in the next step(170 mg).

[0551] Step 3:Methyl(6-hydroxy-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate.

[0552] To a solution of the product of Step 2 (170 mg, 0.56 mmol) inCH₂Cl₂ (5 mL) at 0° C. was added slowly BBr₃ 1.0 M in dichloromethane(2.8 mL, 2.8 mmol) dropwise. The reaction mixture was warmed to r.t. for30 minutes then cooled to −78° C., quenched with MeOH (5 mL), extractedwith CH₂Cl₂, and washed with a saturated aqueous solution of NaHCO₃. Thecombined organic layers were dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel chromatography to give the titlecompound (130 mg).

[0553] Step 4:Methyl[6-(benzyloxy)-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0554] To the compound of Step 3 (130 mg, 0.45 mmol) in DMF (2 mL) at 0°C., was added benzyl bromide (100 mL) and Cs₂CO₃ (300 mg, 0.92 mmol).The reaction mixture was warmed to r.t for 1 hour. The reaction wasquenched with saturated aqueous NH₄Cl and extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel chromatography to give the titlecompound (130 mg).

[0555] Step 5:Methyl{6-(benzyloxy)-9-[(4-chlorophenyl)thio]-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate

[0556] The procedure of Example 25, Step 4 was followed using thecompound of Step 4 (130 mg, 0.34 mmol) in DMF (4 mL) to give the titlecompound (100 mg).

[0557] Step 6:(+/−)-{6-(benzyloxy)-9-[(4-chlorophenyl)thio]-8-isopropyl-2,3dihydro-1H-pyrrolo[1,2-a]indol-yl]acetic acid

[0558] To a solution of the ester of Step 5 100 mg in THF/MeOH (3/1)mixture at r.t. was added in LiOH aqueous solution 1.0 mL. The reactionmixture was stirred at r.t. for 1 hour then AcOH was added and thesolvent was evaporated. The residue was taken up in EtOAc/H₂O and theorganic phase was washed with brine, dried (MgSO₄), filtered andevaporated. The residue was purified by silica gel chromatography,eluting with 1% AcOH in EtOAc to give 70 mg of the title compound.

[0559]¹H NMR (acetone d6) δ 1.10(m 3H), 1.15(m, 3H), 2.45(m, 1H),2.60(m, 1H), 2.95 (m, 1H), 3.18 (m, 1H), 3.80 (m, 1H), 4.15(m, 2H),4.29(m, 1H), 5.18(s, 2H), 6.80(s, 1H), 6.94 (s, 1H), 7.06(d, 2H),7.25(d, 2H), 7.38(m, 1H), 7.42(m, 2H), 7.55(d, 2H).

EXAMPLE 28

[0560](+/−)-{9-[(4-chlorophenyl)thio]-8-isopropyl-6-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0561] The procedures of Example 27, Steps 1, 2, 5 and 6 were followedusing the product of Example 22, Step 5 to provide the title compound.

[0562]¹H NMR (acetone d6) δ 1.18(m 3H), 1.22(m, 3H), 2.32(m, 1H),2.60(m, 1H), 2.85(m, 1H), 3.15(m, 1H), 3.72 (m, 3H), 3.98(s, 1H),4.33(m, 1H), 4.45(m, 1H), 4.65(m, 1H) 7.00(m, 1H), 7.08(m, 3H), 7.25(m,2H),

EXAMPLE 29

[0563](+/−)-[6-(4-chlorophenyl)-9-[(4-chlorophenyl)thio]-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0564] Step 1:Methyl(8-(methylsulfonyl)-6-{[(trifluoromethylsulfonyl]oxy}-2,3-dihydro-1H-pyrrolo[1,2-a]indol-yl)acetate

[0565] To methyl[6-hydroxy-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 23, Step 2, 74 mg, 0.28 mmol) in CH₂Cl₂ (3 mL) at 0° C. wasadded pyridine (28 μL, 0.36 mmol) followed by Tf₂O (77 μl, 0.46 mmol).The reaction mixture was then stirred for 1 hour at r.t. The reactionwas quenched with a saturated solution of NaHCO₃ and extracted withCH₂Cl₂. The combined organic layers were dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography togive the title compound (63 mg).

[0566] Step 2:Methyl(9-[(4-chlorophenyl)thio]-8-(methylsulfonyl)-6-{[(trifluoro-methyl)sulfonyl]oxy}-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[0567] The procedure of Example 25, Step 4 was followed using thecompound of Step 1 (63 mg, 0.14 mmol) in DMF (1 mL) to give the titlecompound (53 mg).

[0568] Step 3:Methyl[6-(4-chlorophenyl)-9-[(4-chlorophenyl)thio]-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0569] To the compound of Step 2 (53 mg, 0.089 mmol) in toluene/EtOH 3:1mixture (4 mL) was added 4-chlorophenylboronic acid (28 mg, 0.18 mmol),K₂CO₃ (18 mg, 0.13 mmol), and tetrakis (triphenylphosphine) palladium(0) (5.1 mg, 0.04 mmol). The reaction mixture was stirred at 80° C.overnight. The reaction was quenched with saturated aqueous NH₄Cl andextracted with EtOAc. The combined organic layers were dried over Na₂SO₄and concentrated. The residue was purified by silica gel chromatographyto provide the title compound (40 mg)

[0570] Step 4:(+/−)-[6-(4-chlorophenyl)-9-[(4-chlorophenyl)thio]-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0571] Starting from the product of Step 3 (40 mg, 0.07 mmol) the titlecompound (35 mg) was synthesized following the procedures described inStep 5 of Example 25.

[0572]¹H NMR (acetone d₆) δ 2.52(m 1H), 2.70(m, 1H), 3.05 (m, 1M),3.20(m, 1H), 3.25 (s, 3H), 3.75 (m, 1H), 4.40(m, 1 h), 4.55(m 1H),7.04(m, 2H), 7.20 (m, 2H), 7.55 (m, 2H), 7.80(m, 2H), 8.15 (m, 2H).

EXAMPLE 30

[0573](+/−)-{8-bromo-9-[(4-chlorophenyl)thio]-6-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0574] Step 1: 2-bromo-4-iodo-1-methylbenzene

[0575] To a vigorously stirred mixture of 3-bromo-4-methylaniline (40 g,215 mmol), sulfuric acid (360 mL) and H₂O (900 mL) at 0° C. was addeddropwise a 30 NaNO₂ solution (16.6 g, 240 mmol in 80 mL of H₂O). Themixture was stirred at 0° C. for 1 hour and a solution of potassiumiodide (64 g, 387 mmol in 160 mL of H₂O) was added. The reaction wasstirred for 8 hours at r.t. The aqueous layer was extracted with Et₂Oand the combined organic layers were washed with a 10% aqueous solutionof Na₂S₂O₃, dried over Na₂SO₄ and concentrated. The residue was filteredthrough a silica gel pad eluted with 10% EtOAc/hexane and concentratedto give 60 g of the title compound as a reddish syrup used as such.

[0576] Step 2:(+/−)-{8-bromo-9-[(4-chlorophenyl)thio]-6-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0577] Starting from 2-bromo-4-iodo-1-methylbenzene, the title compoundwas synthesized by following the procedures described in Steps 1-10 ofExample 7.

[0578] MS (−APCI) m/z 560.1 (M−H)⁻.

EXAMPLE 31

[0579](+/−)-{8-bromo-9-[(4-chlorophenyl)thio]-6-cyano-2,3-dihydro-1H-pyrrolo[1,2-a]indol-yl}aceticacid

[0580] Step 1: (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-cyano-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate

[0581] To a solution of (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate(see Example 30, 2.5 g, 4.3 mmol) in DMF (40 ml) were added zinc cyanide(1.27 g, 10.8 mmol), tris-(dibenzylideneacetone)dipalladium(0) (197 mg,0.21 mmol), H₂O (43 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (120mg, 0.21 mmol), and N₂ was bubbled for 2 minutes into the mixture. Thereaction mixture was stirred for 10 hours at r.t. and poured into 1N HCland extracted with EtOAc. The combined organic layers were washed withbrine and dried over Na₂SO₄ and concentrated. The residue was purifiedby silica gel chromatography eluted with 20% EtOAc/hexane to give 1.6 gof a pale yellow solid.

[0582] MS (+APCI) m/z 476.9 M+H)⁺.

[0583] Step 2:(+/−)-{8-bromo-9-[(4-chlorophenyl)thio]-6-cyano-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0584] The compound of Step 1 was hydrolyzed following the proceduresdescribed in Step 10 of Example 7 to give the title compound.

[0585] MS (−APCI) m/z 460.4 (M−H)⁻.

EXAMPLE 32

[0586] (+/−)-[8-bromo-9-[(4-chlorophenylthio]-6-(2-methyl-2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0587] Step 1: (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)thio]-6-(2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0588] To a solution of (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-cyano-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate(example 31, Step 1, 200 mg, 0.42 mmol) in toluene (3 mL) was addedazidotributyltin (279 mg, 0.84 mmol). The reaction mixture was stirredat 90° C. for 16 hours, AcOH (1 mL) was added and the reaction wasstirred for 2 hours and concentrated. The residue was swished inacetone/hexane 1:2 to give 160 mg of the title compound as a white solidused as such for next reaction.

[0589] Step 2:(+/−)-[8-bromo-9-[(4-chlorophenyl)thio]-6-(2-methyl-2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0590] A solution of the product of Step 1 (160 mg) in THF (5 mL) wastreated with an excess of CH₂N₂ at 0° C. The reaction mixture wasstirred for 5 minutes and the solvent removed. The residue was purifiedby silica gel chromatography eluted with 80% EtOAc/hexane to give 130 mgof methyl ester of the title compound as a white solid, which washydrolyzed following the procedures described in Steps 10 of Example 7to give the title compound.

[0591] MS (−APCI) m/z 517.8 (M−H)⁻.

EXAMPLE 33

[0592](+/−)-[8-bromo-9-[(4-chlorophenyl)thio]-6-(1-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0593] From Step 2 of Example 32 were isolated 30 mg of (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)thio]-6-(1-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetateas a white solid and hydrolyzed following the procedures described inSteps 10 of Example 7.

[0594] MS (−APCI) m/z 518.0 (M−H)⁻.

EXAMPLE 34

[0595](+/−)-[8-bromo-9-[(4-chlorophenyl)thio]-6-(1-methyl-1H-pyrrol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0596] To a solution of (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate(see Example 30, 145 mg, 0.25 mmol) in DMF (3 mL) were addedtris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.025 mmol), triphenylarsine (31 mg, 0.1 mmol) and 1-methyl-2-(tributylstannyl)-1H-pyrrole(111 mg, 0.3 mmol). The mixture was degassed and stirred at r.t. for 2hours. The reaction mixture was poured into 1N HCl and extracted withEtOAc. The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated. The residue was purified by silica gelchromatography eluted with 15% EtOAc/hexane to give methyle ester of thetitle compound which was hydrolyzed following the procedures describedin Step 10 of Example 7.

[0597] MS (−APCI) m/z 513.5 (M−H)⁻.

EXAMPLE 35

[0598](+/−)-{8-acetyl-9-[(4-chlorophenyl)thio]-6-cyano-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0599] Starting from (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-cyano-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate(Example 31, Step 1), the title compound was synthesized following theprocedures described in Steps 1 and 2 of Example 10.

[0600] MS (−APCI) m/z 423.5 (M−H)⁻.

EXAMPLE 36

[0601](+/−)-[8-acetyl-9-[(4-chlorophenyl)thio]-6-(2-methyl-2H-tetrazol-5-yl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0602] Step 1:(+/−)-[8-acetyl-9-[(4-chlorophenyl)thio]-6-(2-methyl-2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid

[0603] Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)thio]-6-(2-methyl-2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(see Example 32), the title compound was synthesized following theprocedures described in Steps 1 and 2 of Example 10.

[0604] MS (−APCI) m/z 479.9 (M−H)⁻.

EXAMPLE 37

[0605](+/−)-[9-[(4-chlorophenyl)thio]-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0606] Step 1: (+/−)-methyl[6-fluoro-8-(methylthio)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0607] To a solution of(+/−)-(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid (Example 7A, Step 1, 400 mg, 1.3 mmol) in THF (10 mL) at −78° C.was added 3M MeMgBr (1.5 mmol) followed by the addition of n-BuLi (2.6mmol, 1.6M solution). The reaction mixture was stirred at −78° C. for 5minutes and an excess of methyl disulfide (300 mg) was added. Thereaction mixture was warmed to r.t. and stirred for 15 minutes and 1NHCl was added. The phases were separated and the aqueous layer wasextracted with EtOAc. The combined organic layers were dried over Na₂SO₄and concentrated. The residue was dissolved in THF and the solution wascooled to 0° C. and treated with an excess of CH₂N₂. The reactionmixture was stirred for 5 minutes and the solvent removed to give 380 mgof the title compound as a pale yellow syrup used as such.

[0608] Step 2: (+/−)-methyl[6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0609] To a solution of the compound of Step 1 (400 mg, 1.4 mmol) inMeOH (20 mL) at r.t. was added sodium tungstate dihydrate (225 mg, 0.7mmol) and 30% H₂O₂ (1.4 mL, 13.6 mmol). The mixture was stirred for 3hours at r.t. and excess of dimethyl sulfide was added. The solvent wasremoved and the residue was purified by silica gel chromatography elutedwith 20% EtOAc/toluene to give 300 mg of the title compound as a paleyellow oil.

[0610] Step 3:(+/−)-[9-[(4-chlorophenyl)thio]-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0611] Starting from the compound of Step 2, the title compound wassynthesized following the procedures described in Steps 9 and 10 ofExample 7.

[0612] MS (−APCI) m/z 451.9 (M−H)⁻.

EXAMPLE 37A

[0613][(1R)-9-[(4-chlorophenyl)thio]-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0614] Step 1:[(1R)-9-[(4-chlorophenyl)thio]-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0615] The title compound was isolated from racemic(+/−)-[9-[(4-chlorophenyl)thio]-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]-aceticacid by preparative HPLC on a chiralpak A/D preparative column elutedwith 35% iPrOH/hexane containing 0.2% AcOH. The title compound wasidentified as the enantiomer with the shorter retention time (lesspolar).

[0616] MS (−APCI) m/z 451.9 (M−H)⁻.

EXAMPLE 38

[0617](+/−)-[9-[(4-chlorophenyl)thio]-8-(ethylsulfonyl)-6-fluoro-2,3-dihydro-1Hpyrrolo[1,2-a]indol-1-yl]acetic acid

[0618] Step 1: (+/−)-methyl[8-(ethylthio)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0619] The procedure described in Example 37, Step 1 was followed usingethyl disulfide (300 mg) instead of methyl disulfide to give 450 mg ofthe title compound as a pale yellow syrup used as such.

[0620] Step 2:(+/−)-[9-[(4-chlorophenyl)thio]-8-(ethylsulfonyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0621] Starting from the compound of Step 1, the title compound wassynthesized following the procedures described in Step 2 of Example 37and Steps 9 and 10 of Example 7.

[0622] MS (−APCI) m/z 465.9 (M−H)⁻.

EXAMPLE 39

[0623][(1R)-9-[(4-chlorophenyl)thio]-6-fluoro-8-(1-methyl-1H-pyrrol-2-yl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0624] Step 1:(4S)-4-benzyl-3-{[9-[(4-chlorophenyl)thio]-6-fluoro-8-(1-methyl-1H-pyrrol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetyl}-1,3-oxazolidin-2-one

[0625] To a solution of(4S)-4-benzyl-3-({8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetyl)-1,3-oxazolidin-2-one(Example 7A, Step 3, 230 mg, 0.38 mmol) in DMF (4 mL) were addedtris(dibenzylideneacetone)dipalladium(0) (37 mg, 0.04 mmol), triphenylarsine (49 mg, 0.16 mmol) and 1-methyl-2-(tributylstannyl)-1H-pyrrole(211 mg, 0.57 mmol). The mixture was degassed and stirred at 90° C. for4 hours. The reaction was poured in 1N HCl and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatographyeluted with 20% EtOAc/toluene to give 240 mg of the title compound as anorange oil.

[0626] Step 2:[(1R)-9-[(4-chlorophenyl)thio]-6-fluoro-8-(1-methyl-1H-pyrrol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0627] Starting from the compound of Step 1, the title compound wassynthesized following the procedures described in Step 4 of Example 7A.

[0628] MS (−APCI) m/z 453.2 (M−H)⁻.

EXAMPLE 40

[0629]{9-[(4-chlorophenyl)thio]-6-fluoro-8-propyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0630] To a solution of[9-[(4-chlorophenyl)thio]-6-fluoro-8-(1-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid (Example 19, 36 mg, 0.08 mmol) in CH₂Cl₂ were added trifluoroaceticacid (0.5 mL) and triethylsilane (0.2 mL). The mixture was stirred for 1hour at r.t. and solvent was removed. The residue was purified by silicagel chromatography eluted with 40% EtOAc/hexane containing 1% of AcOH togive 10 mg the title compound as a white foam.

[0631] MS (−APCI) m/z 416.1 (M−H)⁻.

EXAMPLE 41

[0632](+/−)-{9-[(4-chlorophenyl)thio]-8-ethyl-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0633] Step 1: (+/−)-methyl[9-[(4-chlorophenyl)thio]-6-fluoro-6-8-(1-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0634] To a solution of[9-[(4-chlorophenyl)thio]-6-fluoro-8-(1-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid (85 mg) in THF at 0° C. was added an excess of CH₂N₂. The reactionwas stirred for 5 minutes and the solvent was removed to give 85 mg ofthe title compound as a pale yellow oil used as such.

[0635] Step 2:(+/−)-{9-[(4-chlorophenyl)thio]-8-ethyl-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0636] To a solution of (+/−)-methyl[9-[(4-chlorophenyl)thio]-6-fluoro-8-(1-hydroxyethyl)-2,3-dihydro-1H-pytrolo[1,2-a]indol-1-yl]acetate(see Example 14, 85 mg) in CH₂Cl₂ were added trifluoroacetic acid (0.5mL) and triethylsilane (0.2 mL). The mixture was stirred for 1 hour atr.t. and solvent was removed. The residue was purified by silica gelchromatography eluted with 30% EtOAc/hexane to give 70 mg of the titlecompound as a white foam which has hydrolyzed following the proceduresdescribed in Step 10 of Example 7.

[0637] MS (−APCI) m/z 402.1 (M−H)⁻.

EXAMPLE 42

[0638](+/−)-{9-[(4-chlorophenyl)thio]-6-fluoro-8-isopropenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0639] To a solution of (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate(200 mg, 0.43 mmol) in DMF (4 mL) were addedtris(dibenzylideneacetone)dipalladium(0) (37 mg, 0.04 mmol), triphenylarsine (49 mg, 0.16 mmol) and tributyl(isopropenyl)stannane (285 mg,0.86 mmol). The mixture was degassed and stirred at 90° C. for 4 hours.The reaction was poured in 1N HCl and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatographyeluted with 30% EtOAc/hexane to give (+/−)-methyl{9-[(4-chlorophenyl)thio]-6-fluoro-8-isopropenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetatewhich was hydrolyzed following the procedures described in Step 10 ofExample 7.

[0640] MS (−APCI) m/z 414.3 (M−H)⁻.

EXAMPLE 43

[0641](+/−)-[9-[(4-chlorophenyl)thio]-6-fluoro-8-(1-methyl-1H-pyrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0642] Starting from (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate(Example 7, Step 9, 200 mg, 0.43 mmol) and1-methyl-5-(tributylstannyl)-1H-pyrazole (239 mg, 0.64 mmol), the titlecompound was synthesized following the procedures described in Example42 and Step 10 of Example 7.

[0643] MS (−APCI) m/z 454.2 (M−H)⁻.

EXAMPLE 44

[0644](+/−)-{9-[(4-chlorophenyl)thio]-6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0645] Step 1: (+/−)-methyl(6-fluoro-8-isopropenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[0646] To bromo(isopropenyl)magnesium (21.5 mmol, 4.2M THF solution) wasadded zinc bromide (4.84 g. 21.5 mmol) dissolved in THF (15 mL). Themixture was stirred at 60° C. for 2 hours, cooled to r.t. anddichloro[1,1′-bis(diphenyl phosphino)ferrocene] palladium (II)dichloromethane adduct (112 mg, 0.15 mmol) and copper iodide (41 mg,0.21 mmol) were added. The mixture was stirred for 2 minutes at r.t. anda solution of (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8, 1 g, 3.1 mmol in 5 mL of THF) was added. Thereaction mixture was stirred at 55° C. for 2 hours, cooled to r.t.,poured into 1N HCl and extracted with EtOAc. The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated. The residuewas purified by silica gel chromatography eluted with 20% EtOAc/hexaneto give 600 mg of the title compound as a pale yellow oil.

[0647] Step 2: (+/−)-methyl(6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[0648] A mixture of the compound of Step 1 (600 mg) and 100 mg of Pd/C(10% w/w) in EtOH (7 mL) was shaken under 50 psi of H₂ for 1 hour. Themixture was then filtered through a silica gel pad eluted with EtOAc andthe filtrate was concentrated to give 600 mg of the title compound as apale yellow oil.

[0649] Step 3:(+/−)-{9-[(4-chloropheny)thio]-6-fluoro-8-isopropropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetic acid

[0650] Starting from the compound of Step 2, the title compound wassynthesized following the procedures described in Steps 9 and 10 ofExample 7.

[0651] MS (−APCI) m/z 416.2 (M−H)⁻.

EXAMPLE 44A

[0652]{(1R)-9-[chlorophenyl)thio]-6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0653] Step 1:methyl[(1R)-6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0654] Starting from[(1R)-8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid (from Step 1 of Example 62A) which was converted to methyl[(1R)-8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetateby addition of CH₂N₂, the title compound was synthesized following theprocedures described in Steps 1 and 2 of Example 44.

[0655] Step 2:{(1R)-9-[(4-chlorophenyl)thio]-6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0656] Starting from the compound of Step 1, the title compound wassynthesized following the procedures described in Steps 9 and 10 ofExample 7.

[0657] MS (−APCI) m/z 416.2 (M−H)⁻.

EXAMPLE 45

[0658](+/−)-{9-[(4-chlorophenyl)thio]-8-cyclopent-1-en-1-yl-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0659] Starting from tributyl(cyclopent-1-en-1-yl)stannane the titlecompound was synthesized following the procedures described in Example42 and Step 10 of Example 7.

[0660] MS (−APCI) m/z 440.2 (M−H)⁻.

EXAMPLE 46

[0661](+/−)-(Z/E)-{9-[(4-chlorophenyl)thio]-8-[1-ethylprop-1-enyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0662] Starting from (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate(300 mg, 0.64 mmol) and (Z/E)-tributyl[1-ethylprop-1-enyl]stannane (300mg, 0.84 mmol), the title compound was synthesized following theprocedures described in Example 42 and Step 10 of Example 7.

[0663] MS (−APCI) m/z 442.3 (M−H)⁻.

EXAMPLE 47

[0664](+/−)-[9-[(4-chlorophenylthio]-8-(1-ethylpropyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0665] Step 1: (+/−)-methyl[8-(1-ethyl-1-hydroxypropyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0666] To a solution of(+/−)-(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid (Example 7A, Step 1, 500 mg, 1.6 mmol) in THF (10 mL) at −78° C.was added 3M MeMgBr (1.9 mmol) followed by the addition of n-BuLi (4.8mmol, 1.6M solution). The reaction mixture was stirred at −78° C. for 5minutes and an excess of 3-pentanone (700 mg) was added. The reactionmixture was warmed to r.t. and stirred for 15 minutes. 1N HCl was added,the phases were separated and the aqueous layer was extracted withEtOAc. The combined organic layers were dried over Na₂SO₄ andconcentrated. The residue was dissolved in THF and the solution wascooled to 0° C. and treated with an excess of CH₂N₂. The reactionmixture was stirred for 5 minutes and the solvent removed to give 480 mgof an yellow oil containing ˜30% of the title compound and 70% of methyl(6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate used as such.

[0667] Step 2: (+/−)-methyl[8-(1-ethylpropyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0668] To a solution of the mixture of Step 1 (480 mg) in CH₂Cl₂ wereadded trifluoroacetic acid (1.5 mL) and triethylsilane (0.6 mL). Themixture was stirred for 1 hour at r.t. and the solvent was removed. Theresidue was purified by silica gel chromatography eluted with 10%EtOAc/hexane to give 140 mg of the title compound as a colorless oil.

[0669] Step 3:(+/−)-[9-[(4-chlorophenyl)thio]-8-(1-ethylpropyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid

[0670] Starting from the compound of Step 2, the title compound wassynthesized following the procedures described in Steps 9 and 10 ofExample 7.

[0671] MS (−APCI) m/z 444.3 (M−H)⁻.

EXAMPLE 48

[0672](+/−)-[9-[(4-chlorophenyl)thio]-8-cyclopentyl-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0673] Step 1: (+/−)-methyl(8-cyclopent-1-en-1-yl-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[0674] Starting from (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8, 300 mg, 0.92 mmol) andtributyl(cyclopent-1-en-1-yl)stannane, the title compound (150 mg) wassynthesized as described in Example 42 as a pale yellow oil.

[0675] Step 2: (+/−)-methyl(8-cyclopentyl-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[0676] A mixture of the compound of Step 1 (150 mg) and 70 mg of Pd/C(10% w/w) in EtOH (7 mL) was shaken under 50 psi of H₂ for 12 hours. Themixture was then filtered through a silica gel pad eluted with EtOAc andthe filtrate was concentrated. The residue was purified by silica gelchromatography eluted with 10% EtOAc/hexane to give 90 mg of the titlecompound as an yellow oil.

[0677] Step 3:(+/−)-{9-[(4-chlorophenyl)thio]-8-cyclopentyl-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0678] Starting from the compound of Step 2, the title compound wassynthesized following the procedures described in Steps 9 and 10 ofExample 7.

[0679] MS (−APCI) m/z 442.2 (M−H)⁻.

EXAMPLE 49

[0680](+/−)-{9-[(4-chlorophenyl)thio]-6-fluoro-8-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0681] Starting from (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate(200 mg, 0.43 mmol) and tributyl(phenyl)stannane the title compound wassynthesized following the procedures described in Example 42 and Step 10of Example 7.

[0682] MS (−APCI) m/z 450.0 (M−H)⁻.

EXAMPLE 50

[0683](+/−)-{9-[(4-chlorophenyl)thio]-6-fluoro-8-thien-2-yl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0684] Starting from (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetateand tributyl(thien-2-yl)-stannane, the title compound was synthesizedfollowing the procedures described in Example 42 and Step 10 of Example7.

[0685] MS (−APCI) m/z 456.1 (M−H)⁻.

EXAMPLE 51

[0686](+/−)-[9-[(4-chlorophenyl)thio]-6-fluoro-8-(3-methylthien-2-YL)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0687] Starting from (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetateand tributyl(3-methylthien-2-yl)stannane, the title compound wassynthesized following the procedures described in Example 42 and Step 10of Example 7.

[0688] MS (−APCI) m/z 470.0 (M−H)⁻.

EXAMPLE 52

[0689](+/−)-{9-[(4-chlorophenyl)thio]-6-fluoro-8-vinyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0690] Starting from (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetateand tributyl(vinyl)stannane, the title compound was synthesizedfollowing the procedures described in Example 42 and Step 10 of Example7.

[0691]¹H NMR (acetone-d₆) δ 7.86-7.80 (1H, m), 7.22 (2H, dd), 7.15-7.10(2H, m), 7.04 (2H, dd), 5.70 (1H, d), 5.12 (1H, d), 4.34-4.29 (1H, m),4.21-4.15 (1H, m), 3.83-3.78 (1H, m), 3.14 (1H, dd), 3.01-2.93 (1H, m),2.63 (1H, dd), 2.49-2.41 (1H, m).

EXAMPLE 53

[0692](+/−)-{8-bromo-9-[(4-chlorophenyl)thio]-6-vinyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0693] To a solution of methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate(see Example 30, 200 mg, 0.35 mmol) in DMF (3 mL) were addedtris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.035 mmol), triphenylarsine (43 mg, 0.14 mmol) and tributyl(vinyl)stannane (166 mg, 0.53mmol). The mixture was degassed and stirred at r.t. for 12 hours. Thereaction was poured in 1N HCl and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatographyeluted with 20% EtOAc/hexane to give (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-vinyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}-acetatewhich was hydrolyzed following the procedures described in Steps 10 ofExample 7.

[0694] MS (−APCI) m/z 460.3 (M−H)⁻.

EXAMPLE 54

[0695](+/−)-{9-[(4-chlorophenyl)thio]-6-fluoro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetic acid

[0696] Step 1: (+/−)-methyl{6-fluoro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate

[0697] To a solution of(+/−)-(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid (300 mg, 1 mmol) in THF (7 mL) at −78° C. was added 3M MeMgBr (1.2mmol) followed by the addition of n-BuLi (3 mmol, 1.6M solution). Thereaction was stirred at −78° C. for 5 minutes and an excess of1,1,1,3,3,3-hexafluoroacetone (700 mg) was added. The reaction waswarmed to −40° C. and stirred for 15 minutes. 1N HCl was added, thephases were separated and the aqueous layer was extracted with EtOAc.The combined organic layers were dried over Na₂SO₄ and concentrated. Theresidue was dissolved in THF and the solution was cooled to 0° C. andtreated with an excess of CH₂N₂. The reaction was stirred for 5 min andthe solvent removed. The residue was purified by silica gelchromatography eluted with 20% EtOAc/hexane to 180 mg of the titlecompound as colorless oil.

[0698] Step 2:(+/−)-9-[(4-chlorophenyl)thio]-6-fluoro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}-aceticacid

[0699] Starting from the compound of Step 1, the title compound wassynthesized following the procedures described in Steps 9 and 10 ofExample 7.

[0700] MS (−APCI) m/z 540.3 (M−H)⁻.

EXAMPLE 55

[0701](+)-{9-[(4-chlorophenyl)thio]-6-fluoro-8-thien-3-yl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0702] Starting from (+)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetateand tributyl(thien-3-yl)stannane, the title compound was synthesizedfollowing the procedures described in Example 42 and Step 10 of Example7.

[0703] MS (−APCI) m/z 455.9 (M−H)⁻.

EXAMPLE 56

[0704](+/−)-[9-[(4-chlorophenyl)thio]-6-cyclopropyl-8-(1-methyl-1H-pyrrol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0705] Step 1: (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-cyclopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate

[0706] To a solution of (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-vinyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate(see Example 53, 100 mg) in THF (3 mL) were added CH₂N₂ (excess) andpalladium (II) acetate (5 mg). The reaction mixture was stirred for 30minutes and the addition of reagents was repeated twice. The mixture wasstirred for 2 hours at r.t. and filtered through a silica gel pad elutedwith EtOAc and the filtrated was concentrated. The residue was purifiedby silica gel chromatography eluted with 20% EtOAc/hexane to give 90 mgof the title compound as a white foam.

[0707] Step 2:(+/−)-[9-[(4-chlorophenyl)thio]-6-cyclopropyl-8-(1-methyl-1H-pyrrol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0708] Starting from the compound of Step 1, the title compound wassynthesized following the procedures described in Example 42 and Step 10of Example 7.

[0709] MS (−APCI) m/z 475.1 (M−H)⁻.

EXAMPLE 57

[0710](+/−)-[9-[(4-chlorophenyl)thio]-8-(1-methyl-1H-pyrrol-2-yl)-6-(2-methyl-2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0711] Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)thio]-6-(2-methyl-2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(see Example 32) and 1-methyl-2-(tributylstannyl)-1H-pyrrole, the titlecompound was synthesized following the procedures described in Example42 and Step 10 of Example 7.

[0712] MS (−APCI) m/z 517.0 (M−H)⁻.

EXAMPLE 58

[0713](+/−)-[9-[(4-chlorophenyl)thio]-6-(2-methyl-2H-tetrazol-5-yl)-8-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0714] Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)thio]-6-(2-methyl-2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetateand tributyl(phenyl)stannane, the title compound was synthesized byfollowing the procedures described in Example 42 and Step 10 of Example7.

[0715] MS (−APCI) m/z 514.0 (M−H)⁻.

EXAMPLE 59

[0716](+/−)-{9-[(4-chlorophenyl)thio]-8-cyclopropyl-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0717] Step 1: (+/−)-methyl(6-fluoro-8-vinyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[0718] To a solution of (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8, 330 mg, 1 mmol) in DMF (4 mL) were addedTris(dibenzylideneacetone)dipalladium(0) (92 mg, 0.1 mmol), triphenylarsine (122 mg, 0.4 mmol) and tributyl(vinyl)stannane (475 mg, 1.5mmol). The mixture was degassed and stirred at 60° C. for 12 hours. Thereaction was poured in 1N HCl and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatographyeluted with 20% EtOAc/hexane to give 200 mg of the title compound as anyellow oil.

[0719] Step 2: (+/−)-methyl(8-cyclopropyl-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[0720] Starting from the compound of Step 1 (100 mg), the title compound(70 mg, colorless oil) was synthesized following the proceduresdescribed in Example 56, Step 1.

[0721] Step 3:(+/−)-{-9-[(4-chlorophenyl)thio]-8-cyclopropyl-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0722] Starting from the compound of Step 2, the title compound wassynthesized following the procedures described in Steps 9 and 10 ofExample 7.

[0723] MS (−APCI) m/z 414.0 (M−H)⁻.

EXAMPLE 60

[0724] (+/−)-methyl[8-bromo-9-(4-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0725] Step 1: (+/−)-methyl[8-bromo-9-(4-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0726] To a mixture of trifluoroacetic acid (79 mg, 0.7 mmol) andtriethylsilane (161 mg, 1.38 mmol) in CH₂Cl₂ (1 mL) at 0° C. was added amixture of (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8, 150 mg, 0.46 mmol) and 4-chlorobenzaldehyde (71 mg,0.51 mmol) in CH₂Cl₂ (3 mL). The mixture was stirred at r.t. for 1 hourand concentrated. The residue was purified by silica gel chromatographyeluted with 20% EtOAc/hexane to give 155 mg of the title compound.

[0727] Step 2:(+/−)-[8-bromo-9-(4-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0728] Starting from the compound of Step 1, the title compound wassynthesized following the procedures described in Step 10 of Example 7.

[0729] MS (−APCI) m/z 436.0 (M−H)⁻.

EXAMPLE 61

[0730](+/−)-[9-(4-chlorobenzoyl)-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0731] Step 1: (+/−)-methyl[8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0732] To a suspension of trichloroaluminum (1.9 g, 14.4 mmol) in 1,2dichloroethane (20 mL) at r.t. was added 4-chlorobenzoyl chloride (2.5g, 14.4 mmol). The mixture was stirred for 5 minutes at r.t. and(+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8, 1.5 g, 4.8 mmol) in 1,2 dichloroethane (10 mL) wasadded. The mixture was stirred at 75° C. for 4 hours, cooled to r.t. andquenched with a solution of aqueous saturated NaHCO₃ and poured into amixture of EtOAc and 1N HCl. The phases were separated and the aqueouslayer was extracted with EtOAc. The combined organic layers were washedwith aqueous saturated NaHCO₃ and brine, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatographyeluted with 30% EtOAc/hexane to give 1.5 g of the title compound as afade yellow solid.

[0733] Step 2:(+/−)-[9-(4-chlorobenzoyl)-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0734] To the compound of Step 1 (100 mg, 0.22 mmol) in1-methyl-2-pyrrolidinone (4 mL) were added methanesulphinic acid sodiumsalt (113 mg, 1.1 mmol) and copper iodide (209 mg, 1.1 mmol). Themixture was degassed and stirred at 130° C. for 3 hours, cooled to r.t.,diluted with EtOAc and filtered through a silica gel pad eluted withEtOAc. The filtrate was washed with brine, dried over Na₂SO₄ andconcentrated to give (+/−)-methyl[9-(4-chlorobenzoyl)-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetatewhich was hydrolyzed following the procedures described in Step 10 ofthe Example 7.

[0735] MS (−APCI) m/z 448.0 (M−H)⁻.

EXAMPLE 62

[0736][(1R)-9-(4-chlorobenzyl)-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0737] Starting from (+/−)-methyl[6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 37, Step 2), the title compound was synthesized following theprocedures described in Step 1 of Example 60 and Step 10 of Example 7.

[0738] MS (−APCI) m/z 434.0 (M−H)⁻.

EXAMPLE 62A

[0739][(1R)-9-(4-chlorobenzyl)-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0740] Step 1:[(1R)-8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0741](+/−)-(8-Bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid (Example 7A, Step 1) was resolved by preparative HPLC on achiralpak A/D preparative column eluted with 5% iPrOH/hexane containing0.2% AcOH. The less polar isomer (shorter retention time) was identifiedas [(1R)-8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid.

[0742] Step 2:methyl[(1R)-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0743] Starting from the compound of Step 1, the title compound wassynthesized following the procedures described in Steps 1 and 2 ofExample 37.

[0744] Step 3:[(1R)-9-(4-chlorobenzyl)-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0745] Starting from the compound of Step 2, the title compound wassynthesized following the procedures described in Step 1 of Example 60and Step 10 of Example 7.

[0746] MS (−APCI) m/z 434.1 (×−H)⁻.

EXAMPLE 63

[0747](+/−)-{9-[(4-chloropheny)thio]-6-fluoro-8-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0748] Step 1: (+/−)-methyl{6-fluoro-8-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate

[0749] To (+/−)-methyl{6-fluoro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate(Example 54, Step 1, 115 mg, 0.28 mmol) in acetonitrile (3 mL) wereadded cesium carbonate (300 mg, 0.9 mmol) and methyl iodide (114 mg, 0.8mmol). The mixture was stirred at 50° C. for 2 hours, filtered through asilica gel pad eluted with 50% EtOAc/hexane and the filtrate wasconcentrated to give 100 mg of the title compound used as such.

[0750] Step 2:(+/−)-{9-[(4-chlorophenyl)thio]-6-fluoro-8-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethy]-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}-aceticacid

[0751] Starting from the compound of Step 1, the title compound wassynthesized following the procedures described in Steps 9 and 10 ofExample 7.

[0752] MS (−APCI) m/z 554.2 (M−H)⁻.

EXAMPLE 64

[0753](+/−)-[9-(4-chlorobenzoyl)-6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0754] Starting from (+/−)-methyl(6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 44, Step 1), the title compound was synthesized following theprocedures described in Step 1 of Example 61 and Step 10 of Example 7.

[0755] MS (−APCI) m/z 412.1 (M−H)⁻.

EXAMPLE 65

[0756](+/−)-[9-(4-chlorobenzoyl)-6-fluoro-8-(1-methyl-1H-pyrrol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0757] Starting from (+/−)-methyl[8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(see Example 69) and 1-methyl-2-(tributylstannyl)-1H-pyrrole, the titlecompound was synthesized following the procedures described in Example42 and Step 10 of Example 7.

[0758] MS (−APCI) m/z 449.1 (M−H)⁻.

EXAMPLE 66

[0759](+/−)-[9-(4-chlorobenzyl)-6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0760] Starting from (+/−)-methyl(6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 44, Step 2), the title compound was synthesized following theprocedures described in Step 1 of Example 60 and Step 10 of Example 7.

[0761] MS (−APCI) m/z 398.0 (M−H)⁻.

EXAMPLE 67

[0762][(1R)-9-(2,4-dichlorobenzyl)-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0763] Starting from methyl[(1R)-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 62A, Step 2, 120 mg, 0.37 mmol) and 2,4-dichlorobenzaldehyde(71 mg, 0.51 mmol), the title compound was synthesized following theprocedures as described in Step 1 of Example 60 and Step 10 of Example7.

[0764] MS (−APCI) m/z 469.9(M−H)⁻.

EXAMPLE 68

[0765][(1R)-9-(2,6-dichlorobenzyl)-6-fluoro-8-(methylsulfonynl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0766] Starting from methyl[(1R)-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 62A, Step 2, 64 mg, 0.2 mmol) and 2,6-dichlorobenzaldehyde (39mg, 0.22 mmol), the title compound was synthesized following theprocedures as described in Step 1 of Example 60 and Step 10 of Example7.

[0767] MS (APCI) m/z 470.0 (M−H)⁻.

EXAMPLE 69

[0768](+/−)-[8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0769] Starting from (+/−)-methyl[8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 61, Step 1), the title compound was synthesized following theprocedures described in Step 10 of Example 7.

[0770] MS (−APCI) m/z 449.9 (M−H)⁻.

EXAMPLE 70

[0771](+/−)-[9-(4-chlorobenzoyl)-8-cyclopropyl-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0772] Starting from (+/−)-methyl[8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 61, Step 1), the title compound was synthesized following theprocedures described in Steps 1 and 2 of Example 59 and Step 10 ofExample 7.

[0773]¹H NMR (acetone-d₆) δ 7.81 (2H, dd), 7.50 (2H, dd), 7.03 (1H, dd),6.56 (1H, dd), 4.27-4.18 (2H, m), 3.69-3.64 (1H, m), 2.95-2.90 (1H, m),2.64 (1H, dd), 2.49 (1H, dd), 2.47-2.41 (1H, m), 1.95-1.87 (1H, m),0.66-0.60 (2H, m), 0.50-0.46 (1H, m), 0.38-0.33 (1H, m).

EXAMPLE 71

[0774](+/−)-[9-(4-chlorobenzoyl)-6-fluoro-8-(1-methoxypropyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0775] Starting from(+/−)-[8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid (Example 69), the title compound was synthesized following theprocedures described in Step 1 of Example 19, Step 1 of Example 20 andStep 10 of Example 7.

[0776] MS (−APCI) m/z 442.1 (M−H)⁻.

EXAMPLE 72

[0777](+/−)-[9-(4-chlorobenzoyl)-6-fluoro-8-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0778] Starting from (+/−)-methyl[8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 61, Step 1, 100 mg, 0.22 mmol) and tributylephenyl)stannane(121 mg, 0.33 mmol), the title compound was synthesized following theprocedures as described in Example 42 and Step 10 of Example 7.

[0779] MS (−APCI) m/z 446.0 (M−H)⁻.

EXAMPLE 73

[0780](+/−)-[9-(4-chlorobenzoyl)-6-fluoro-8-thien-2-yl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0781] Starting from (+/−)-methyl[8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetateand tributyl(thien-2-yl)stannane, the title compound was synthesizedfollowing the procedures described in Example 42 and Step 10 of Example7.

[0782] MS (−APCI) m/z 452.2 (M−H)⁻.

EXAMPLE 74

[0783](+/−)-[6-fluoro-8-(methylsulfonyl)-9-(2,4,6-trichlorobenzyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0784] Step 1: (+/−)-methyl[8-bromo-6-fluoro-9-(2,4,6-trichlorobenzyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0785] Starting from (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo-[1,2-a]indol-1-yl)acetate(Example 7, Step 8, 326 mg, 1 mmol) and 2,4,6-trichlorobenzaldehyde (250mg, 1.2 mmol), the title compound (350 mg) was synthesized following theprocedures described in Step 1 of Example 60.

[0786] Step 2:(+/−)-[6-fluoro-8-(methylsulfonyl)-9-(2,4,6-trichlorobenzyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0787] Starting from the compound of Step 1, the title compound wassynthesized following the procedures described in Step 2 of Example 61and Step 10 of Example 7.

[0788] MS (−APCI) m/z 504.2 (M−H)⁻.

EXAMPLE 75

[0789](+/−)-{6-fluoro-8-(methyldulfonyl)-9-[(2,4,5-trichlorophenyl)thio]-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0790] Step 1: (+/−)-methyl{8-bromo-6-fluoro-9-[(2,4,5-trichlorophenyl)thio]-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate

[0791] Starting from bis(2,4,5-trichlorophenyl) disulfide (638 mg, 1.5mmol) and (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8, 326 mg, 1 mmol), the title compound (70 mg) wassynthesized as described in Step 9 of Example 7.

[0792] Step 2:(+/−)-{6-fluoro-8-(methylsulfonyl)-9-[(2,4,5-trichlorophenyl)thio]-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0793] Starting from the compound of Step 1, the title compound wassynthesized following the procedures described in Step 2 of Example 61and Step 10 of Example 7.

[0794]¹H NMR (acetone-d₆) δ 7.73 (1H, dd), 7.64 (1H, dd), 7.60 (1H, s),6.85 (1H, s), 4.54-4.48 (1H, m), 4.41-4.35 (1H, m), 3.95-3.88 (1H, m);3.43 (3H, s), 3.15-3.04 (2H, m), 2.79 (1H, dd), 2.59-2.53 (1H, m).

EXAMPLE 76

[0795](+/−)-[9-(1,1′-biphenyl-4-ylcarbonyl)-6-fluoro-8-(methylfulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0796] Starting from 4-biphenylcarbonyl chloride (72 mg, 0.33 mmol) and(+/−)-methyl[6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(35 mg, 0.11 mmol) the title compound was synthesized following theprocedures described in Step 1 of Example 61 and Step 10 of Example 7.

[0797] MS (−APCI) m/z 490.2 (M−H)⁻.

EXAMPLE 77

[0798](+/−)-[6-fluoro-8-(methylsulfonyl)-9-(2-naphthoyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0799] Step 1: (+/−)-methyl[8-bromo-6-fluoro-9-(2-naphthoyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0800] Starting from 2-naphthoyl chloride (343 mg, 1.8 mmol) and(+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8, 200 mg, 0.6 mmol) the title compound (250 mg, fadeyellow solid) was synthesized following the procedures described in Step1, Example 61.

[0801] Step 2:(+/−)-[6-fluoro-8-(methylsulfonyl)-9-(2-naphthoyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0802] Starting from the compound of Step 1 (190 mg, 0.4 mmol), thetitle compound was synthesized following the procedures described inStep 2 of Example 61 and Step 10 of the Example 7.

[0803] MS (−APCI) m/z 464.1 (M−H)⁻.

EXAMPLE 78

[0804](+/−)-[8-bromo-6-fluoro-9-(2-naphthoyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0805] Starting from To (+/−)-methyl[8-bromo-6-fluoro-9-(2-naphthoyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 77, Step 1), the title compound was synthesized following theprocedures described in Step 10 of Example 7.

[0806] MS (−APCI) m/z 464.0 (M−H)⁻.

EXAMPLE 79

[0807](+/−)-[9-[(4-chlorophenyl)thio]-6-fluoro-8-(methylsulfonyl)-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0808] Step 1: (4-bromo-6-fluoro-1H-indol-2-yl)methanol

[0809] To a solution of methyl 4-bromo-6-fluoro-1H-indole-2-carboxylate(3 g, 11 mmol) in THF (50 mL) at −30° C. was added diisobutylaluminumhydride (33 mmol, 1.5M toluene solution). The mixture was stirred for 1hour at −30° C. and 1N HCl was added. The phases were separated and theaqueous layer was extracted with Et₂O. The combined organic layers weredried over Na₂SO₄ and concentrated to give 2.6 g of the title compoundused as such.

[0810] Step 2: 4-bromo-6-fluoro-1H-indole-2-carbaldehyde

[0811] To a solution of (4-bromo-6-fluoro-1H-indol-2-yl)methanol (2.6 g,11 mmol) in CH₂Cl₂ (100 mL) at r.t. was added Dess-Martin periodinane(6.4 g, 15 mmol). The mixture was stirred for 30 minutes at r.t. andsaturated aqueous NaHCO₃ was added. The mixture was filtered through acelite pad and the filtrate was extracted with CH₂Cl₂. The combinedorganic layers were dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel chromatography eluted with 30% EtOAc to give 2 gof the title compound.

[0812] Step 3: ethyl-3-(4-bromo-6-fluoro-1H-indol-2-yl)prop-2-enoate

[0813] To a solution of 4-bromo-6-fluoro-1H-indole-2-carbaldehyde (1.8g, 7.4 mmol) in THF (100 mL) at r.t. was added(ethoxycarbonylmethylene)triphenylphosphorane (5 g, 14 mmol). Themixture was stirred for 2 hours at r.t. and the mixture was filteredthrough a silica gel pad eluted with 40% EtOAc and the filtrate wasconcentrated. The residue was purified by silica gel chromatographyeluted with 20% EtOAc to give 1.6 g of the title compound.

[0814] Step 4: (+/−)-ethyl8-bromo-1-(2-ethoxy-2-oxoethyl)-6-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indole-2-carboxylate

[0815] To a solution of diethyl malonate (1.67 g, 10.4 mmol) in EtOH (30mL) at r.t. was added sodium methoxide (2.26 mL, 25% solution in MeOH).The mixture was stirred for 5 minutes and a solution of the compound ofStep 3 (1.3 g, 4.2 mmol) in EtOH (10 mL) was added. The mixture wasstirred at 75° C. for 12 hours, saturated aqueous NH₄Cl was added andthe aqueous layer was extracted with EtOAc. The combined organic layerswere dried over Na₂SO₄ and concentrated. The residue was purified bysilica gel chromatography eluted with 20% EtOAc to give 1.6 g of thetitle compound.

[0816] MS (+APCI) m/z 426.2 (M+H)⁺.

[0817] Step 5: (+/−)-ethyl(8-bromo-6-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[0818] To a solution of the compound of Step 4 (1 g, 2.4 mmol) in DMSO(20 mL) at r.t. were added sodium chloride (420 mg, 7.2 mmol) and H₂O(260 mg, 14.4 mmol). The mixture was stirred at 120° C. for 3 hours,cooled, and partitioned between H₂O and CH₂Cl₂. The aqueous layer wasextracted with CH₂Cl₂ and the combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated to give 900 mg of the titlecompound.

[0819] MS (+APCI) m/z 354.1 (M+H)⁺.

[0820] Step 6: (+/−)-4-ethyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate

[0821] Starting from bis(2,4,5-chlorophenyl) disulfide (2.1, 7.2 mmol)and the compound of Step 5 the title compound (500 mg, as a 60% pureyellow oil) was synthesized following the procedures described in Step 9of Example 7, and the product was used as such.

[0822] Step 7: (+/−)-ethyl[9-[(4-chlorophenyl)thio]-6-fluoro-8-(methylsulfonyl)-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0823] Starting from the product of Step 6 (500 mg, 1.06 mmol) the titlecompound was synthesized following the procedures described in Step 2,Example 61, and the residue was purified by silica gel chromatographyeluted with 40% EtOAc/hexane to give 100 mg of the title compound.

[0824] Step 8:(+/−)-[9-[(4-chlorophenyl)thio]-6-fluoro-8-(methylsulfonyl)-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0825] To the compound of Step 7 (40 mg) in 2-butanone (4 mL) was added6N HCl (0.5 mL). The mixture was stirred at 80° C. for 3 hours, cooledto r.t., diluted with H₂O and the aqueous layer was extracted withEtOAc. The combined organic layers were dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatographyeluted with 40% EtOAc/hexane containing 1% AcOH to give 23 mg of thetitle compound as a white solid.

[0826] MS (−APCI) m/z 466.1 (M−H)⁻.

EXAMPLE 80

[0827](+/−)-[6-fluoro-9-(2-furoyl)-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0828] Starting from (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8) and 2-furoyl chloride, the title compound wassynthesized following the procedures described in Steps 1 and 2 ofExample 61 and Step 10 of Example 7.

[0829] MS (−APCI) m/z 404.1 (M−H)⁻.

EXAMPLE 81

[0830](+/−)-[9-(2,4-dichlorobenzoyl)-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1Hpyrrolo[1,2-a]indol-1-yl]acetic acid

[0831] Starting from (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8) and 2,4-dichlorobenzoyl chloride, the title compoundwas synthesized following the procedures described in Steps 1 and 2 ofExample 61 and Step 10 of Example 7.

[0832] MS (−APCI) m/z 482.0 (M−H)⁻.

EXAMPLE 82

[0833](+/−)-[9-[4-chloro-2-(methylsulfonyl)benzoyl]-6-fluoro-8-(methylsulfonyl)2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0834] Starting from (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8) and 4-chloro-2-iodobenzoyl chloride, the titlecompound was synthesized following the procedures described in Steps 1and 2 of Example 61 and Step 10 of Example 7.

[0835] MS (−APCI) m/z 526.1 (M−H)⁻.

EXAMPLE 83

[0836](+/−)-[8-BROMO-9-(4-CHLORO-2-IODOBENZOYL)-6-FLUORO-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0837] Starting from (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(example 7, Step 8) and 4-chloro-2-iodobenzoyl chloride, the titlecompound was synthesized following the procedures described in Step 1 ofExample 61 and Step 10 of Example 7.

[0838] MS (−APCI) m/z 576.0 (M−H)⁻.

EXAMPLE 84

[0839](+/−)-{9-[2-(AMINOCARBONYL)-4-CHLOROBENZOYL]-8-BROMO-6-FLUORO-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL}ACETICACID

[0840] Step 1: (+/−)-methyl[8-bromo-9-(4-chloro-2-cyanobenzoyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0841] Starting from (+/−)-methyl[8-bromo-9-(4-chloro-2-iodobenzoyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(see Example 83, 150 mg, 0.25 mmol), the title compound (100 mg brownishsolid) was synthesized as described in Step 1 of Example 31.

[0842] Step 2:(+/−)-{9-[2-(aminocarbonyl)-4-chlorobenzoyl]-8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0843] To a solution of the compound of Step 1 (30 mg) in a 3/1 mixtureof THF/MeOH (3 mL) was added 1N LiOH (1 mL, aqueous solution). Thereaction mixture was stirred at r.t. for 16 h and AcOH (0.5 mL) andbrine (5 mL) were added. The aqueous layer was extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄ and concentrated. Theresidue was swished in EtOAc to give 18 mg of the title compound as awhite solid.

[0844] MS (−APCI) m/z 491.0 (M−H)⁻.

EXAMPLE 85

[0845](+/−)-[9-(4-chloro-2-cyanobenzoyl)-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0846] Starting from (+/−)-methyl[8-bromo-9-(4-chloro-2-cyanobenzoyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 84, Step 1), the title compound was synthesized following theprocedures described in Step 2 of Example 61 and Step 10 of Example 7.

[0847] MS (−APCI) m/z 473.3 (M−H)⁻.

EXAMPLE 86

[0848][(1R)-9-(4-CHLORO-2-IODOBENZOYL)-6-FLUORO-8-ISOPROPYL-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0849] Starting from 4-chloro-2-iodobenzoyl chloride (542 mg, 1.8 mmol)and methyl[(1R)-6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 44A, Step 1, 173 mg, 0.6 mmol), the title compound wassynthesized following the procedures described in Step 1 of Example 61and Step 10 of Example 7.

[0850] MS (−APCI) m/z 538.1 (M−H)⁻.

EXAMPLE 87

[0851](+/−)-[9-(1,3-BENZOTHIAZOL-2-YLCARBONYL)-8-BROMO-6-FLUORO-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0852] Starting from (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8) and 1,3-benzothiazole-2-carbonyl chloride, the titlecompound was synthesized following the procedures described in Step 1 ofExample 61 and Step 10 of Example 7.

[0853] MS (−APCI) m/z 472.9 (M−H)⁻.

EXAMPLE 88

[0854]{(1R)-9-[4-CHLORO-2-(METHYLSULFONYL)BENZOYL]-6-FLUORO-8-ISOPROPYL-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL}ACETICACID

[0855] Starting from methyl[(1R)-9-(4-chloro-2-iodobenzoyl)-6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(see Example 86), the title compound was synthesized following theprocedures described in Step 2 of Example 61 and Step 10 of Example 7.

[0856] MS (−APCI) m/z 490.3 (M−H)⁻.

EXAMPLE 89

[0857]((1R)-6-FLUORO-8-(METHYLSULFONYL)-9-{[4-(TRIFLUOROMETHYL)-PHENYL]THIO}-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL)ACETICACID

[0858] Step 1: bis[4-(trifluoromethyl)phenyl]disulfide

[0859] To a solution of 4-(trifluoromethyl)benzenethiol (1 g) in Et₂Owas added bromine until orange color remained. The addition was stoppedand the organic layer was washed with 1:1 aqueous saturatedNaHCO_(3/10)% aqueous Na₂S203, dried over Na₂SO₄ and concentrated togive the title compound used as such.

[0860] Step 2:methyl((1R)-8-bromo-6-fluoro-9-{[4-(trifluoromethyl)phenyl]thio}-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[0861] Starting from bis[4-(trifluoromethyl)phenyl] disulfide (454 mg,1.28 mmol) and methyl[(1R)-8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 62A, 200 mg, 0.64 mmol), the title compound (280 mg, 70% pure)was synthesized as described in Step 9 of Example 7.

[0862] Step 3:((1R)-6-fluoro-8-(methylsulfonyl)-9-{[4-(trifluoromethyl)phenyl]thio}-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid

[0863] Starting from the compound of Step 2, the title compound wassynthesized following the procedures described in Step 2 of Example 61and Step 10 of Example 7.

[0864] MS (−APCI) m/z 486.3 (M−H)⁻.

EXAMPLE 90

[0865]((1R)-6-FLUORO-8-METHYLSULFONYL)-9-{[4-(METHYLSULFONYL)-PHENYL]THIO}-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL)ACETICACID

[0866] Step 1:1-bromo-4-[(4-bromophenyl)dithio]benzene

[0867] Starting from 4-bromobenzenethiol, the title compound wassynthesized following the procedures described in Step 1 of Example 89.

[0868] Step 2:Methyl{(1R)-8-bromo-9-[(4-bromophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate

[0869] Starting from 1-bromo-4-[(4-bromophenyl)dithio]benzene and methyl[(1R)-8-bromo-6-fluoro-2,3-dihydro-1H-pyirolo[1,2-a]indol-1-yl]acetate(Example 62A), the title compound was synthesized following theprocedures described in Step 9 of Example 7.

[0870] Step 3:{(1R)-6-fluoro-8-(methylsulfonyl)-9-{[4-(methylsulfonyl)phenyl]thio}-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid

[0871] Starting from the compound of Step 2, the title compound wassynthesized following the procedures described in Step 2 of Example 61and Step 10 of Example 7.

[0872] MS (−APCI) m/z 496.3 (M−H)⁻.

EXAMPLE 91

[0873](+/−)-[8-BROMO-6-FLUORO-9-(QUINOLIN-2-YLCARBONYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0874] Starting from (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8) and quinoline-2-carbonyl chloride, the titlecompound was synthesized following the procedures described in Step 1 ofExample 61 and Step 10 of Example 7.

[0875] MS (−APCI) m/z 465.2 (M−H)⁻.

EXAMPLE 92

[0876](+/−)-[6-FLUORO-8-(METHYLSULFONYL)-9-(QUINOLIN-2-YLCARBONYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0877] Starting from methyl[8-bromo-6-fluoro-9-(quinolin-2-ylcarbonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(see Example 91), the title compound was synthesized following theprocedures described in Step 2 of Example 61 and Step 10 of Example 7.

[0878] MS (−APCI) m/z 465.2 (M−H)⁻.

EXAMPLE 93

[0879](+/−)-[9-(1,3-BENZOTHIAZOL-2-YLTHIO)-8-BROMO-6-FLUORO-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0880] Step 1: 2-(1,3-benzothiazol-2-yldithio)-1,3-benzothiazole

[0881] Starting from 1,3-benzothiazole-2-thiol, the title compound wassynthesized following the procedures described in Step 1 of Example 89.

[0882] Step 2:(+/−)-[9-(1,3-benzothiazol-2-ylthio)-8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0883] Starting from 2-(1,3-benzothiazol-2-yldithio)-1,3-benzothiazoleand (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8), the title compound was synthesized following theprocedures described in Step 9 of Example 7 and Step 10 of Example 7.

[0884] MS (−APCI) m/z 476.9 (M−H)⁻.

EXAMPLE 94

[0885](+/−)-[9-(1,3-BENZOTHIAZOL-2-YLTHIO)-6-FLUORO-8-(METHYLSULFONYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0886] Starting from methyl[9-(1,3-benzothiazol-2-ylthio)-8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(see Example 93) the title compound was synthesized following theprocedures described in Step 2 of Example 61 and Step 10 of Example 7.

[0887] MS (−APCI) m/z 475.0 (M−H)⁻.

EXAMPLE 95

[0888](+/−)-[9-[(4-CHLOROPHENYL)THIO]-8-(METHYLSULFONYL)-6-(2-METHYL-2H-TETRAZOL-5-YL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]IDOL-1-YL]ACETICACID

[0889] Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)thio]-6-(2-methyl-2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(see Example 32, 70 mg, 0.13 mmol), the title compound was synthesizedfollowing the procedures described in Step 2 of Example 61 and Step 10of the Example 7.

[0890] MS (−APCI) m/z 516.1 (M−H)⁻.

EXAMPLE 96

[0891](+/−)-[9-[1-(4-CHLOROPHENYL)ETHYL]-6-FLUORO-8-(METHYLSULFONYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0892] Step 1: (+/−)-tert-butyl[8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0893] To(+/−)-[8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid (Example 69, 500 mg) in toluene (10 mL) at 100° C. was slowly added1,1-ditert-butoxy-N,N-dimethylmethanamine (0.7 mL). The mixture wasstirred at 110° C. for 1 h, cooled to r.t., washed with aqueoussaturated NaHCO₃ and brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel chromatography eluted with 30%EtOAc/hexane to give 410 mg of the title compound.

[0894] Step 2: (+/−)-tert-butyl{8-bromo-9-[1-(4-chlorophenyl)vinyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate

[0895] To a suspension of methyltriphenylphosphonium bromide (536 mg,1.5 mmol) in THF (7 mL) at r.t. was added potassium tert-butoxide (1.5mL, 1M THF solution). The mixture was stirred for 30 minutes at r.t. anda solution of the compound of Step 1 (190 mg, 0.38 mmol) in THF (7 mL)was added. The reaction mixture was stirred at 60° C. for 2 h, cooledand poured into aqueous saturated NH₄Cl. The phases were separated andthe aqueous layer was extracted with EtOAc. The combined organic layerswere dried over Na₂SO₄ and concentrated. The residue was purified bysilica gel chromatography eluted with 20% EtOAc/hexane to give 150 mg ofthe title compound.

[0896] Step 3: (+/−)-tert-butyl[9-[1-(4-chlorophenyl)vinyl]-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0897] Starting from the compound of Step 2 (108 mg, 0.21 mmol), thetitle compound (80 mg) was synthesized as described in Example 61, Step2 but without carrying out the hydrolysis.

[0898] Step 4: (+/−)-tert-butyl[9-[1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[0899] A mixture of the compound of Step 3 (78 mg) and 20 mg of Pd/C(10% w/w) in EtOH (3 mL) was stirred under H₂ (balloon) for 1 h. Themixture was then filtered through a silica gel pad eluted with EtOAc andthe filtrate was concentrated to give 75 mg of the title compound usedas such.

[0900] Step 4:(+/−)-[9-[1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0901] A mixture of the compound of Step 1 (75 mg) and trifluoroaceticacid (0.9 mL) in CH₂Cl₂ (3 mL) was stirred for 5 h at r.t. andconcentrated. The residue was purified by silica gel chromatographyeluted with 40% EtOAc/hexane containing 1% AcOH to give 35 mg of thetitle compound.

[0902] MS (−APCI) m/z 448.2 (M−H)⁻.

EXAMPLE 97

[0903](+/−)-[9-[(4-CHLOROPHENYL)ACETYL]-6-FLUORO-8-(METHYLSULFONYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0904] Starting from (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8) and (4-chlorophenyl)acetyl chloride, the titlecompound was synthesized following the procedures described in Steps 1and 2 of Example 61 and Step 10 of Example 7.

[0905] MS (−APCI) m/z 462.1 (M−H)⁻.

EXAMPLE 98

[0906](+/−)-[6-FLUORO-8-ISOPROPYL-9-(1-NAPHTHYLTHIO)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-YL]ACETICACID

[0907] Step 1:1-(1-naphthyldithio)naphthalene

[0908] Starting from naphthalene-1-thiol, the title compound wassynthesized following the procedures described in Step 1 of Example 89.

[0909] Step 2:(+/−)-[6-fluoro-8-isopropyl-9-(1-naphthylthio)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0910] Starting from 1-(1-naphthyldithio)naphthalene and (+/−)-methyl(6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 44, Step 1), the title compound was synthesized following theprocedures described in Step 9 of Example 7 and Step 10 of Example 7.

[0911] MS (−APCI) m/z 432.0 (M−H)⁻.

EXAMPLE 99

[0912](+/−)-[6-FLUORO-8-ISOPROPYL-9-(2-NAPHTHYLTIHO)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0913] Step 1: 2-(2-naphthyldithio)naphthalene

[0914] Starting from naphthalene-2-thiol, the title compound wassynthesized following the procedures described in Step 1 of Example 89.

[0915] Step 2:(+/−)-[6-fluoro-8-isopropyl-9-(2-naphthylthio)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0916] Starting from 2-(2-naphthyldithio)naphthalene and (+/−)-methyl(6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 44, Step 1), the title compound was synthesized following theprocedures described in Step 9 of Example 7 and Step 10 of Example 7.

[0917] MS (−APCI) m/z 432.0 (M−H)⁻.

EXAMPLE 100

[0918](+/−)-[8-BROMO-6-FLUORO-9-PYRIMIDIN-2-YLTHIO)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0919] Step 1: 2-(pyrimidin-2-yldithio)pyrimidine

[0920] Starting from pyrimidine-2-thiol, the title compound wassynthesized following the procedures described in Step 1 of Example 89.

[0921] Step 2:(+/−)-[8-bromo-6-fluoro-9-(pyrimidin-2-ylthio)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0922] Starting from 2-(pyrimidin-2-yldithio)pyrimidine and (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8), the title compound was synthesized following theprocedures described in Step 9 of Example 7 and Step 10 of Example 7.

[0923] MS (−APCI) m/z 420.0 (M−H)⁻.

EXAMPLE 101

[0924](+/−)-[6-FLUORO-8-(METHYLSULFONYL)-9-(PYRIMIDIN-2-YLTHIO)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0925] Starting from methyl[8-bromo-6-fluoro-9-(pyrimidin-2-ylthio)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(see Example 100), the title compound was synthesized following theprocedures described in Step 2 of Example 61 and Step 10 of Example 7.

[0926] MS (−APCI) m/z 420.0 (M−H)⁻.

EXAMPLE 102

[0927](+/−)-[9-[2-(4-CHLOROPHENYL)ETHYL]-6-FLUORO-87(METHYLSULFONYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0928] Step 1: (+/−)-methyl{8-bromo-9-[2-(4-chlorophenyl)ethyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate

[0929] To a mixture of trifluoroacetic acid (79 mg, 0.7 mmol) andtriethylsilane (161 mg, 1.38 mmol) in CH₂Cl₂ (1 mL) at 0° C. was added amixture of (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8, 150 mg, 0.46 mmol) and (4-chlorophenyl)acetaldehyde(85 mg, 0.55 mmol) in CH₂Cl₂ (3 mL). The mixture was stirred at r.t. for1 h and concentrated. The residue was purified by silica gelchromatography eluted with 30% EtOAc/hexane to give 190 mg of the titlecompound.

[0930] Step 2:(+/−)-[9-[2-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0931] Starting from the compound of Step 1, the title compound wassynthesized following the procedures described in Step 2 of Example 61and Step 10 of Example 7.

[0932] MS (−APCI) m/z 448.1 (M−H)⁻.

EXAMPLE 103

[0933](+/−)-[9-[(4-CHLOROPHENYL)THIO]-8-(1-METHOXYPROPYL)-6-(2-METHYL-2H-TETRAZOL-5-YL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0934] Starting from(+/−)-[8-bromo-9-[(4-chlorophenyl)thio]-6-(2-methyl-2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid (Example 32), the title compound was synthesized following theprocedures described in Example 19, Step 1 of Example 20 and Step 10 ofExample 7.

[0935] MS (−APCI) m/z 510.1 (M−H)⁻.

EXAMPLE 104

[0936][(1R)-6-FLUORO-8-ISOPROPYL-9-(2-NAPHTHOYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-YL]ACETICACID

[0937] Starting from methyl[(1R)-6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 44A, Step 1) and 2-naphthoyl chloride, the title compound wassynthesized following the procedures described in Step 1′ of Example 61and Step 10 of Example 7.

[0938] MS (−APCI) m/z 428.2 (M−H)⁻.

EXAMPLE 105

[0939](+/−)-[6-FLUORO-8-(METHYLSULFONYL)-9-(2-NAPHTHYLTHIO)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0940] Starting from 2-(2-naphthyldithio)naphthalene and (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 7, Step 8), the title compound was synthesized following theprocedures described in Step 9 of Example 7, Step 2 of Example 61 andStep 10 of Example 7.

[0941] MS (−APCI) m/z 468.1 (M−H)⁻.

EXAMPLE 106

[0942] (+/−)-{9-[(4-CHLORO-2-FLUOROPHENYL)THIO]-6-FLUORO-8-ISOPROPYL2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL}ACETIC ACID

[0943] Step 1: bis(4-chloro-2-fluorophenyl)disulfide

[0944] Starting from 4-chloro-2-fluorobenzenethiol, the title compoundwas synthesized following the procedures described in Step 1 of Example89.

[0945] Step 2:(+/−)-{9-[(4-chloro-2-fluorophenyl)thio]-6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0946] Starting from bis(4-chloro-2-fluorophenyl) disulfide and(+/−)-methyl(6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 44, Step 1), the title compound was synthesized following theprocedures described in Steps 9 and 10 of Example 7.

[0947] MS (−APCI) m/z 434.1 (M−H)⁻.

EXAMPLE 107

[0948](+/−)-[9-[(4-CHLORO-2-FLUOROPHENYL)THIO]-6-FLUORO-8-(METHYLSULFONYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0949] Starting from bis(4-chloro-2-fluorophenyl) disulfide and(+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(example 7, Step 8), the title compound was synthesized following theprocedures described in Step 9 of Example 7, Step 2 of Example 61 andStep 10 of Example 7.

[0950] MS (−APCI) m/z 470.0 (M−H)⁻.

EXAMPLE 108

[0951](+/−)-[9-[(4-CHLOROPHENYL)THIO]-6-FLUORO-8-(2-METHYLPHENYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0952] To (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 7, Step 9, 100 mg, 0.21 mmol) in 1-propanol (2 mL) were added2-methylphenylboronic acid (57 mg, 0.42 mmol), 3:1 mixture oftriphenylphosphine/palladium (>) acetate (11 mg) and 2M aqueouspotassium carbonate (0.3 mL). The mixture was degassed and stirred at80° C. for 6 h and the reaction mixture was cooled to r.t. Then THF (3mL) and 1N LiOH were added and the mixture was stirred for 2 h at r.t.AcOH (0.5 mL) and brine were added and the aqueous layer was extractedwith EtOAc. The combined organic layers were dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatographyeluted with 40% EtOAc/hexane containing 1% AcOH to give 90 mg of thetitle compound.

[0953] MS (−APCI) m/z 464.0 (M−H)⁻.

EXAMPLE 109

[0954](+/−)-{9-[(4-CHLOROPHENYL)THIO]-6-FLUORO-8-QUINOLIN-8-YL-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL}ACETICACID

[0955] Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 7, Step 9) and quinolin-8-ylboronic acid, the title compoundwas synthesized following the procedures described in Example 108.

[0956] MS (−APCI) m/z 501.3 (M−H)⁻.

EXAMPLE 110

[0957](+/−)-{8-(1-BENZOTHIEN-3-YL)-9-[(4-CHLOROPHENYL)THIO]-6-FLUORO-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL}ACETICACID

[0958] Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 7, Step 9) and 1-benzothien-3-ylboronic acid, the titlecompound was synthesized following the procedures described in Example108.

[0959] MS (−APCI) m/z 506.1 (M−H)⁻.

EXAMPLE 111

[0960](+/−)-[9-[(4-CHLOROPHENYL)THIO]-8-(3,5-DIMETHYLISOXAZOL-4-YL)-6-FLUORO-2,3-DIHYDRO—1H-PYRROLO[1,2-a]INDOL-1-YL]ACETIC ACID

[0961] Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1.12-a]indol-1-yl]acetate(Example 7, Step 9) and 3,5-dimethylisoxazol-4-ylboronic acid, the titlecompound was synthesized following the procedures described Example 108.

[0962] MS (−APCI) m/z 469.0 (M−H)⁻.

EXAMPLE 112

[0963](+/−)-[9-[(4-CHLOROPHENYL)THIO]-6-FLUORO-8-(4-METHYLTHIEN-3-YL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0964] Step 1:4,4,5,5-tetramethyl-2-(4-methylthien-3-yl)-1,3,2-dioxaborolane

[0965] To a solution of 3-bromo-4-methylthiophene (600 mg, 3.4 mmol) inDMF (12 mL) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (908 mg, 3.6mmol), potassium acetate (1 g, 10.2 mmol) anddichloro[1,1′-bis-(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (73 mg, 0.1 mmol). The reaction mixture wasdegassed and stirred at 8° C. for 4 h, cooled and poured in brine. Theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated. The residue waspurified by short silica gel chromatography eluted with 10% EtOAc/hexaneto give 500 mg of the title compound used as such.

[0966] Step 2:(+/−)-[9-[(4-chlorophenyl)thio]-6-fluoro-8-(4-methylthien-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0967] Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 7, Step 9) and4,4,5,5-tetramethyl-2-(4-methylthien-3-yl)-1,3,2-dioxaborolane, thetitle compound was synthesized following the procedures describedExample 108.

[0968] MS (−APCI) m/z 470.0 (M−H)⁻.

EXAMPLE 113

[0969](+/−)-{9-[(4-CHLOROPHENYL)THIO]-6-FLUORO-8-[3-(1H-PYRAZOL-1-YL)PHENYL]-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL}ACETICACID

[0970] Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 7, Step 9) and 3-(1H-pyrazol-1-yl)phenylboronic acid, the titlecompound was synthesized following the procedures described Example 108.

[0971] MS (−APCI) m/z 516.3 (M−H)⁻.

EXAMPLE 114

[0972](+/−)-[9-[(4-CHLOROPHENYL)TIHO]-6-FLUORO-8-(2-FORMYLTHIEN-3-YL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-YL]ACETICACID

[0973] Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 7, Step 9) and 2-formylthien-3-ylboronic acid, the titlecompound was synthesized following the procedures described in Example108.

[0974] MS (−APCI) m/z 484.2 (M−H)⁻.

EXAMPLE 115

[0975](+/−)-[9-[(4-CHLOROPHENYL)THIO]-6-FLUORO-8-(2-METHOXYPHENYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0976] Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 7, Step 9) and 2-methoxyphenylboronic acid, the title compoundwas synthesized following the procedures described in Example 108.

[0977] MS (−APCI) m/z 480.1 (M−H)⁻.

EXAMPLE 116

[0978](+/−)-[9-[(4-chlorophenyl)thio]-8-(3,4-dichlorophenyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[0979] Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 7, Step 9) and 3,4-dichlorophenylboronic acid, the titlecompound was synthesized following the procedures described in Example108.

[0980] MS (−APCI) m/z 518.1(M−H)⁻.

EXAMPLE 117

[0981](+/−)-{9-[(4-chlorophenyl)thio]-6-fluoro-8-quinolin-6-yl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[0982] Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 7, Step 9) and quinolin-6-ylboronic acid, the title compoundwas synthesized following the procedures described in Example 108.

[0983] MS (−APCI) m/z 501.1(M−H)⁻.

EXAMPLE 118

[0984](+/−)-[9-[(4-CHLOROPHENYL)THIO]-6-FLUORO-8-(2-NAPHTHYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0985] Staring from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 7, Step 9) and 2-naphthylboronic acid, the title compound wassynthesized following the procedures described in Example 108.

[0986] MS (−APCI) m/z 500.2 (M−H)⁻.

EXAMPLE 119

[0987](+/−)-{9-[(4-CHLOROPHENYL)THIO]-8-CYANO-6-FLUORO-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL}ACETICACID

[0988] The title compound was synthesized from (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate(Example 7, Step 9, 500 mg, 1.07 mmol) using the procedure as describedin Step 1 of Example 31 but carrying out the reaction at 90° C. for 12hours, and Step 10 of Example 7.

[0989] MS (−APCI) m/z 399.0 (M−H)⁻.

EXAMPLE 120

[0990](+/−)-[6-FLUORO-8-ISOPROPYL-9-(1-NAPHTHOYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0991] Starting from methyl(6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 44, Step 2) and 1-naphthoyl chloride, the title compound wassynthesized following the procedures described in Step 1 of Example 61and Step 10 of Example 7.

[0992] MS (−APCI) m/z 428.1 (M−H)⁻.

EXAMPLE 121

[0993](+/−)-[9-(3,4-DICHLOROBENZOYL)-6-FLUORO-8-ISOPROPYL-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[0994] Starting from methyl(6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 44, Step 2) and 3,4-dichlorobenzoyl chloride, the titlecompound was synthesized following the procedures described in Step 1 ofExample 61 and Step 10 of Example 7.

[0995] MS (−APCI) m/z 446.1 (M−H)⁻.

EXAMPLE 122

[0996](+/−)-{10-[(4-CHLOROPHENYL)THIO]-3-FLUORO-1-ISOPROPYL-6,7,8,9-TETRAHYDROPYRIDO[1,2-a]INDOL-9-YL}ACETICACID

[0997] Step 1: methyl4-bromo-1-(4-ethoxy-4-oxobutyl)-6-fluoro-1H-indole-2-carboxylate

[0998] To a solution of methyl 4-bromo-6-fluoro-1H-indole-2-carboxylate(10 g, 36.8 mmol) in DMF (100 mL) at 0° C. was added NaH (1.8 g, 44.2mmol, 60% in oil). The mixture was stirred at r.t. for 30 minutes andtetra-n-butylammonium iodide (500 mg) was added, followed by theaddition of ethyl 4-bromobutyrate (10.1 g, 51.5 mmol). The reactionmixture was stirred at r.t. for 3 h, poured into saturated aqueous NH₄Cland the aqueous layer was extracted with EtOAc. The combined organiclayers were washed with brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel chromatography eluted with 20% EtOActo give 13.2 g of the title compound.

[0999] Step 2: (+/−)-ethyl1-bromo-3-fluoro-9-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxylate

[1000] To a solution of the compound of Step 1 (13.2 g, 34.1 mmol) inTHF (100 mL) at 0° C. was added potassium t-butoxide (34.1 mmol, 1M THFsolution). The mixture was stirred at 0° C. for 2 h, poured into 1N HCland the aqueous layer was extracted with EtOAc. The combined organiclayers were washed with brine, dried over Na₂SO₄, concentrated andswished in EtOAc to give 11.6 g of the title compound.

[1001] Step 3: (+/−)-methyl(1-bromo-3-fluoro-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate

[1002] Starting from the compound of Step 2, the title compound wassynthesized following the procedures described in Steps 6-8 of Example7.

[1003] Step 4: (+/−)-methyl(3-fluoro-1-isopropyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate

[1004] Starting from the compound of Step 3, the title compound wassynthesized following the procedures described in Steps 1 and 2 ofExample 44.

[1005] Step 5:(+/−)-{10-[(4-chlorophenyl)thio]-3-fluoro-1-isopropyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl}aceticacid

[1006] Starting from the compound of Step 4, the title compound wassynthesized following the procedures described in Steps 9 and 10 ofExample 7.

[1007] MS (−APCI) m/z 430.0 (M−H)⁻.

EXAMPLE 123

[1008](+/−)-[3-FLUORO-1-ISOPROPYL-10-(2-NAPHTHOYL)-6,7,8,9-TETRAHYDROPYRIDO[1,2-a]INDOL-9-YL]ACETICACID

[1009] Starting from (+/−)-methyl(3-fluoro-1-isopropyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate(Example 122, Step 4) and 2-naphthoyl chloride, the title compound wassynthesized following the procedures described in Step 1 of Example 61and Step 10 of Example 7.

[1010] MS (−APCI) m/z 442.2 (M−H)⁻.

EXAMPLE 124

[1011](+/−)-[10-(4-CHLOROBENZOYL)-3-FLUORO-1-ISOPROPYL-6,7,8,9-TETRAHYDROPYRIDO[1,2-a]INDOL-9-YL]ACETICACID

[1012] Starting from (+/−)-methyl(3-fluoro-1-isopropyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate(Example 122, Step 4) and 4-chlorobenzoyl chloride, the title compoundwas synthesized following the procedures described in Step 1 of Example61 and Step 10 of Example 7.

[1013] MS (−APCI) m/z 426.0 (M−H)⁻.

EXAMPLE 125

[1014](+/−)-[10-[(4-CHLOROPHENYL)THIO]-3-FLUORO-1-METHYLSULFONYL)-6,7,8,9-TETRAHYDROPYRIDO[1,2-a]INDOL-9-YL]ACETICACID

[1015] Starting from bis(4-chlorophenyl) disulfide and (+/−)-methyl(1-bromo-3-fluoro-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate(Example 122, Step 3), the title compound was synthesized following theprocedures described in Step 9 of Example 7, Step 2 of Example 61 andStep 10 of Example 7.

[1016] MS (−APCI) m/z 466.0 (M−H)⁻.

EXAMPLE 126

[1017](+/−)-[9-(1,1′-BIPHENYL-4-YL)-6-FLUORO-8-METHYLSULFONYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[1018] Step 1: (+/−)-methyl[9-bromo-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[1019] To a solution of (+/−)-methyl[6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 37, Step 2, 256 mg, 0.79 mmol) in THF (5 mL) at 0° C. was addedNBS (169 mg, 0.95 mmol). The mixture was stirred for 10 minutes at 0° C.and poured into aqueous 10% sodium thiosulfate. The aqueous layer wasextracted with EtOAc. The combined organic layers were washed withsaturated aqueous NaHCO₃ and brine, dried over Na₂SO₄ and concentratedto give 320 mg of the title compound used as such.

[1020] Step 2:(+/−)-[9-(1,1′-biphenyl-4-yl)-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[1021] To a solution of the compound of Step 1 (60 mg, 0.15 mmol) in DMF(3 mL) at r.t. were added 1,1′-biphenyl-4-ylboronic acid (60 mg, 0.3mmol), cesium fluoride (68 mg, 0.45 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]-palladium (II)dichloromethane adduct (11 mg, 0.015 mmol). The mixture was degassed andstirred at 80° C. for 12 h, cooled to r.t. and 1N HCl was added. Theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with brine, dried over. Na₂SO₄ and concentrated. The residue waspurified by silica gel chromatography eluted with 40% EtOAc/hexane togive 40 mg of the methyl ester of the title compound, which washydrolyzed following the procedures described in Step 10 of Example 7.

[1022] MS (−APCI) m/z 462.2 (M−H)⁻.

EXAMPLE 127

[1023](+/−)-[6-FLUORO-8-(METHYLSULFONYL)-9-(2-NAPHTHYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[1024] Starting from 2-naphthylboronic acid and (+/−)-methyl[9-bromo-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 126, Step 1), the title compound was synthesized following theprocedures described in Step 2 of Example 126 and Step 10 of Example 7.

[1025] MS (−APCI) m/z 436.1 (M−H)⁻.

EXAMPLE 128

[1026](+/−)-[9-(1,1′-BIPHENYL-3-YL)-6-FLUORO-8-(METHYLSULFONYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[1027] Starting from 1,1′-biphenyl-3-ylboronic acid and (+/−)-methyl[9-bromo-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 126, Step 1), the title compound was synthesized following theprocedures described in Step 2 of Example 126 and Step 10 of Example 7.

[1028] MS (−APCI) m/z 462.2 (M−H)⁻.

EXAMPLE 129

[1029](+/−)-{9-[(4-chlorophenyl)thio]-6-cyano-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[1030] Step 1: (+/−)-methyl(8-isopropyl-6-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[1031] Starting from (+/−)-methyl(8-bromo-6-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(Example 22, Step 5, 1 g, 2.96 mmol in 5 mL of THF) and using theprocedure described in Example 44, Steps 1 and 2, the title compound(800 mg) was obtained.

[1032] Step 2: (+/−)-methyl(6-hydroxy-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[1033] To a solution of the compound of Step 1 (800 mg, 2.65 mmol) inCH₂Cl₂ (10 mL) at 0° C. was added boron tribromide (13.3 mmol, 1Msolution in CH₂Cl₂). The mixture was stirred at 0° C. for 5 minutes,cooled to −78° C. and MeOH (2 mL) was added. The mixture was poured intosaturated aqueous NaHCO₃ and the aqueous layer was extracted with EtOAc.The combined organic layers were washed with brine, dried over Na₂SO₄and concentrated. The residue was purified by silica gel chromatographyeluted with 40% EtOAc/hexane to give 525 mg of the title compound.

[1034] Step 3: (+/−)-methyl(8-isopropyl-6-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[1035] To a solution of the compound of Step 2 (510 mg, 1.78 mmol) inCH₂Cl₂ (10 mL) at 0° C. were added pyridine (211 mg, 2.6 mmol) andtriflic anhydride (604 mg, 2.14 mmol). The mixture was stirred at r.t.for 2 h and poured into saturated aqueous NaHCO₃. The aqueouslayer wasextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated to give the title compoundused as such.

[1036] Step 4: (+/−)-methyl(9-[(4-chlorophenyl)thio]-8-isopropyl-6-{[(trifluoromethyl)-sulfonyl]oxy}-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

[1037] The title compound was synthesized from the compound of Step 3using the procedure described in Example 7, Step 9.

[1038] Step 5:(+/−)-(9-[(4-chlorophenyl)thio]-6-cyano-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid

[1039] The title compound was synthesized from the compound of Step 4using the procedures described in Step 1 of Example 31 but carrying outthe reaction at 80° C. for 2 hrs., and Step 10 of Example 7.

[1040] MS (−APCI) m/z 423.1 (M−H)⁻.

EXAMPLE 130

[1041](+/−)-[9-[(4-CHLOROPHENYL)THIO]-8-ISOPROPYL-6-(2-METHYL-2H-TETRAZOL-5-YL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[1042] Step 1: (+/−)-methyl[9-[(4-chlorophenyl)thio]-8-isopropyl-6-(2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[1043] To a solution of(+/−)-{9-[(4-chlorophenyl)thio]-6-cyano-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}aceticacid (Example 129, 400 mg, 0.91 mmol) in toluene (5 mL) was addedazidotributyltin (604 mg, 1.82 mmol). The reaction was stirred at 110°C. for 24 h, AcOH (2 mL) was added and the reaction was stirred for 2 hand concentrated and used as such.

[1044] Step 2: (+/−)-methyl[9-[(4-chlorophenyl)thio]-8-isopropyl-6-(2-methyl-2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[1045] A solution of the compound of Step 1 in THF (10 mL) was treatedwith an excess of CH₂N₂ at 0° C. The reaction mixture was stirred for 5minutes and the solvent removed. The residue was purified by silica gelchromatography eluted with 50% EtOAc/hexane to give 65 mg of(+/−)-methyl[9-[(4-chlorophenyl)thio]-8-isopropyl-6-(2-methyl-2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetateand 150 mg of (+/−)-methyl[9-[(4-chlorophenyl)thio]-8-isopropyl-6-(1-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate.

[1046] Step 3:(+/−)-[9-[(4-chlorophenyl)thio]-8-isopropyl-6-(2-methyl-2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[1047] Starting from the compound of Step 2 the title compound wassynthesized following the procedures described in Step 10 of Example 7.

[1048] MS (−APCI) m/z 480.1 (M−H)⁻.

EXAMPLE 131

[1049](+/−)-[9-[(4-CHLOROPHENYL)TIEO]-8-ISOPROPYL-6-(1-METHYL-1H-TETRAZOL-5-YL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[1050] Starting from (+/−)-methyl[9-[(4-chlorophenyl)thio]-8-isopropyl-6-(1-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(Example 130, Step 2), the title compound was synthesized following theprocedures described in Step 10 of Example 7.

[1051] MS (−APCI) m/z 480.1 (M−H)⁻.

EXAMPLE 132

[1052](+/−)-[9-[(4-CHLOROPHENYL)THIO]-6,8-BIS(METHYLSULFONYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[1053] Starting from (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate(see Example 30, Step 2), the title compound was synthesized followingthe procedures described in Step 2 of Example 61 and Step 10 of Example7.

[1054] MS (−APCI) m/z 512.0 (M−H)⁻.

EXAMPLE 133

[1055](+/−)-[9-[(4-CHLOROPHENYL)THIO]-8-(1-METHYL-1H-PYRROL-2-YL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[1056] Step 1: (+/−)-Methyl{8-bromo-9-[(4-chlorophenyl)thio]-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate.

[1057] A mixture of (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate(see Example 30, Step 2, 125 mg) and 10 mg of Pd/C (10% w/w) in EtOAc (3mL) and MeOH (7 mL) was shaken under 30 psi of H₂ for 48 h. The mixturewas then filtered through a short pad of celite and the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with 25% EtOAc/hexane to give 66 mg of the titlecompound.

[1058] Step 2: (+/−)-Methyl[9-[(4-chlorophenyl)thio]-8-(1-methyl-1H-pyrrol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate.

[1059] Starting with the compound of Step 1, the title compound wassynthesized following the procedures described in Step 1 of Example 39.

[1060] Step 3:(+/−)-[9-[(4-Chlorophenyl)thio]-8-(1-methyl-1H-pyrrol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[1061] From the compound of Step 2, the title compound was synthesizedfollowing the procedures described in Step 10 of Example 7.

[1062] MS (−APCI) m/z 435.2 (M−H)⁻.

EXAMPLE 134

[1063](+/−)-{9-[(4-CHLOROPHENYL)THIO]-6-FLUORO-8-PYRIDIN-3-YL-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL}ACETICACID

[1064] (+/−)-Methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate wasallowed to react with 3-(1,3,2-dioxaborinan-2-yl)pyridine under theconditions described in Example 108 to give the title compound.

[1065] MS (−APCI) m/z 451.0 (M−H)⁻, m/z 453.0 (+H)⁺.

EXAMPLE 135

[1066](+/−)-[9-[(4-CHLOROPHENYL)THIO]-5,6-DIFLUORO-8-(1-METHYL-1H-PYRROL-2-YL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[1067] Step 1: 2-Bromo-4,5-difluorobenzoic acid

[1068] To a 0° C. slurry of CuBr₂ (7.4 g, 33.2 mmol) in CH₃CN (150 mL)was added tert-BuONO (5.2 mL, 43.3 mmol). 2-Amino-4,5-difluorobenzoicacid was then added portion wise over 5 min and the resulting mixturewas allowed to stir for 2 h. at 0° C. followed by 16 h. at roomtemperature. The reaction mixture was concentrated in vacuo to 50% ofits volume, quenched with excess 1N HCl, and extracted with i-Pr₂O (3×30mL). The combined organic layers were extracted with 1 N NaOH (3×30 mL).This aqueous phase was acidified with excess 1N HCl and re-extractedwith i-Pr₂O (3×30 mL). The combined organic layers were washed withbrine, dried over MgSO₄ and concentrated in vacuo to give the crudebromo acid (6.5 g) that was used without further purification.

[1069] Step 2: 2-Bromo-4,5-difluorobenzaldehyde

[1070] To a 0° C. THF (20 mL) solution of crude2-bromo-4,5-difluorobenzoic acid (6.5 g) was slowly added BH₃ THF (35.6mmol). The solution was stirred overnight at +4° C. Excess aqueous K₂CO₃was added and the mixture was extracted with Et₂O (2×40 mL). Thecombined organic layers were washed with H₂O, brine, and dried overMgSO₄. Evaporation of the volatiles gave the crude benzyl alcohol (6.7g) as an oil. This residue was treated overnight with MnO₂ (13.2 g, 152mmol) in refluxing EtOAc (40 mL). More MnO₂ was added (12.0 g, 138 mmol)and the mixture was refluxed for another 24 h. Filtration through ashort pad of celite/silica gel and concentration afforded a oilyresidue. Purification by flash chromatography on silica gel eluting with15% Et₂O/hexane gave 2.65 g of the desired benzaldehyde as a beigesolid.

[1071] Step 3: (+/−)-Methyl{8-bromo-9-[(4-chlorophenyl)thio]-5,6-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate

[1072] Starting with the compound of Step 2, the title compound wassynthesized following the procedures described in Steps 3 to 9 ofExample 7.

[1073] Step 4:(+/−)-[9-[(4-Chlorophenyl)thio]-5,6-difluoro-8-(1-methyl-1H-pyrrol-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[1074] Starting from the compound of Step 3, the title compound wassynthesized following the procedures described in Step 1 of Example 39and Step of Example 7.

[1075] MS (−APCI) m/z 471.2 (M−H)⁻.

EXAMPLE 136

[1076](+/−)-[9-[(4-CHLOROPHENYL)THIO]-5,6-DIFLUORO-8-(METHYLSULFONYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[1077] Step 1: (+/−)-Methyl[9-[(4-chlorophenyl)thio]-5,6-difluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[1078] To (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-5,6-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate(Example 135, Step 3, 300 mg, 0.62 mmol) in 1-methyl-2-pyrrolidinone (6mL) were added methanesulphinic acid sodium salt (315 mg, 3.1 mmol) andcopper iodide (587 mg, 3.1 mmol). The mixture was purged with nitrogenand stirred at 140° C. for 4.5 h, cooled to room temperature, dilutedwith excess EtOAc and filtered through a silica gel pad eluted withEtOAc. The filtrate was washed with brine, dried over MgSO₄, andconcentrated to a oily residue. Purification by silica gel flashchromatography eluting with 25% to 60% EtOAc/hexane afforded the desiredmono-methylsulphonyl derivative (90 mg).

[1079] Also isolated from this reaction were the following by-products:(+/−)-methyl{8,9-bis[(4-chlorophenyl)thio]-5,6-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate,60 mg, and (+/−)-methyl[9-[(4-chlorophenyl)thio]-6-fluoro-5,8-bis(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate,80 mg.

[1080] Step 2:[9-[(4-Chlorophenyl)thio]-5,6-difluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[1081] The compound of Step 1 was hydrolyzed following the proceduresdescribed in Step 10 of Example 7.

[1082] MS (−APCI) m/z 469.9 (M−H)⁻.

EXAMPLE 137

[1083](+/−)-{8,9-BIS[(4-CHLOROPHENYL)THIO]-5,6-DIFLUORO-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL}ACETICACID

[1084] (+/−)-Methyl{8,9-bis[(4-chlorophenyl)thio]-5,6-difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate(isolated as a by-product from step 1 of Example 136, 60 mg) washydrolyzed following the procedures described for Step 10 of Example 7to give the title compound.

[1085] MS (−APCI) m/z 533.8 (M−H)⁻.

EXAMPLE 138

[1086](+/−)-[9-[(4-CHLOROPHENYL)THIO]-6-FLUORO-5,8-BIS(METHYLSULFONYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[1087] (+/−)-Methyl[9-[(4-chlorophenyl)thio]-6-fluoro-5,8-bis(methyl-sulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(isolated as a by-product from step 1 of Example 136, 20 mg) washydrolyzed by stirring overnight with IN LiOH aq. (0.5 mL) in a mixtureof THF (1 mL) and 1,4-dioxane (1 mL). The reaction was quenched withexcess 1M NaH₂PO₄ aq. and extracted with EtOAc (3×15 mL). The combinedorganic extracts were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The solid residue was stirred 30 min in 1:1mixture of acetone and Et₂O and filtered to give the title compound (9mg) as a white solid.

[1088] MS (−APCI) m/z 530.0 (M−H)⁻.

EXAMPLE 139

[1089](+/−)-[9-[(4-CHLOROPHENYL)THIO]-6-METHOXY-5,8-BIS(METHYLSULFONYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[1090] Step 1: (+/−)-Methyl[9-[(4-chlorophenyl)thio]-6-methoxy-5,8-bis(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate

[1091] (+/−)-Methyl[9-[(4-chlorophenyl)thio]-6-fluoro-5,8-bis(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate(isolated as a by-product from step 1 of Example 136, 60 mg), wasstirred at 60° C. for 1 h in 0.1 N MeONa in

[1092] MeOH (2 mL) and 1,4-dioxane (2 mL). Excess 1 N NaH₂PO₄ was addedand the mixture was extracted with EtOAc (3×). The combined organiclayers were dried over MgSO₄. Purification by silica gel flashchromatography eluting with 40% to 70% EtOAc/hexane gave the desiredcompound (39 mg).

[1093] Step 2:(+/−)-[9-[(4-Chlorophenyl)thio]-6-methoxy-5,8-bis(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[1094] The compound of Step 1 was dissolved in MeOH (2 mL) and1,4-dioxane (2 mL) and treated with IN LiOH for 2 h at room temperature.Addition of 1 N NaH₂PO₄ (3 mL) and 1 N HCl (0.4 mL) led to a suspensionthat was filtered through paper. The solid was air dried overnightyielding 14 mg of the title compound as a white solid.

[1095] MS (−APCI) m/z 541.8 (M−H)⁻.

EXAMPLE 140

[1096](+/−)-[9-[(4-CHLOROPHENYL)THIO]-5-FLUORO-8-(METHYLSULFONYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL]ACETICACID

[1097] Step 1: (+/−)-Methyl{8-bromo-9-[(4-chlorophenyl)thio]-5-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate

[1098] Starting from 2-bromo-5-fluorotoluene, the title compound wassynthesized following the procedures described in Steps 1 to 9 ofExample 7.

[1099] Step 2:(+/−)-[9-[(4-Chlorophenyl)thio]-5-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]aceticacid

[1100] Starting from the compound of Step 1, the title compound wassynthesized following the procedures described in Step 2 of Example 61and Step 10 of Example 7.

[1101] MS (−APCI) m/z 452.0 (M−H)⁻.

EXAMPLE 141

[1102](+/−)-{8-BROMO-9-[(4-CHLOROPHENYL)THIO]-6-FLUORO-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL}(DIFLUORO)ACETICACID

[1103] Step 1: (+/−)-Ethyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}(difluoro)acetate

[1104] Starting from8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (Example 7,Step 6) and ethyl bromo(difluoro)acetate, the title compound wassynthesized following the procedures described in Steps 7 to 9 ofExample 7.

[1105] Step 2:(+/−)-{8-Bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}(difluoro)acetic acid

[1106] The ethyl ester (65 mg) from Step 1 was dissolved in 2 mL of old(peroxide containing) 1,4-dioxane. 1 N LiOH was added (0.25 mL) and themixture was stirred at room temperature for 2 h. Excess 1 N NaH₂PO₄ wasadded and the mixture was extracted with EtOAc (2×). The combinedorganic layers were washed with brine, dried over MgSO₄ and concentratedin vacuo. Purification by silica gel chromatography on preparativeplates eluting with 25% EtOH/CH₂CL₂+3% AcOH gave the desired compound(32 mg).

[1107] MS (−APCI) m/z 488.0, 489.9 (M−H)⁻.

EXAMPLE 142

[1108](+/−)-{8-BROMO-9-[(4-CHLOROPHENYL)SULFINYL]-6-FLUORO-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL}(DIFLUORO)ACETICACID

[1109] Two diastereoisomers of the title compound (13 mg and 10 mg) wereisolated from Step 2 of Example 141.

[1110] MS (−APCI) m/z 504.0, 506.1 (M−H)⁻.

EXAMPLE 143

[1111](+/−)-[9-[(4-CHLOROPHENYL)THIO]-6-FLUORO-8-(METHYLSULFONYL)-2,3-DIHYDRO-1H-PYRROLO[1,2-a]INDOL-1-YL](DIFLUORO)ACETICACID

[1112] Starting from (+/−)-ethyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}(difluoro)acetate(Example 141, Step 1) the title compound was synthesized following theprocedures described in Step 2 of Example 61.

[1113] MS (−APCI) m/z 488.0 (M−H)⁻.

EXAMPLE 144

[1114](+/−)-[10-(4-CHLOROBENZOYL)-3-FLUORO-1-(METHYLSULFONYL)-6,7,8,9-TETRAHYDROPYRIDO[1,2-a]INDOL-9-YL]ACETICACID

[1115] Step 1: (+/−)-Methyl[3-fluoro-1-(methylsulfonyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]acetate

[1116] Starting from methyl(1-bromo-3-fluoro-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate(Example 122, Step 3) the title compound was synthesized following theprocedures described in Step 1 of Example 136.

[1117] Step 2:(+/−)-[10-(4-Chlorobenzoyl)-3-fluoro-1-(methylsulfonyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]aceticacid

[1118] The compound of Step 1 was acylated following the proceduresdescribed in Step 1 of Example 61 and hydrolyzed as in Step 10 ofExample 7.

[1119] MS (−APCI) m/z 462.1 (M−H)⁻.

EXAMPLE 145

[1120](+/−)-[3-FLUORO-1-(METHYLSULFONYL)-10-(2-NAPHTHOYL)-6,7,8,9-TETRAHYDROPYRIDO[1,2-a]INDOL-9-YL]ACETICACID

[1121] Starting from (+/−)-methyl[3-fluoro-1-(methylsulfonyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]acetate(Example 144, Step 1) the title compound was acylated following theprocedures described in Step 1 of Example 61 and hydrolyzed as in Step10 of Example 7.

[1122] MS (−APCI) m/z 478.1 M−H)⁻.

[1123] The following compounds were prepared according to the generalmethodologies indicated, each of which has been exemplified in theprevious examples:

Ex. R² R³ Y¹ Ar p Meth. MS* 146 F (CH₃)₂CH C(O) 3-Br-4-Cl—Ph 2 3,10504.1 147 F (CH₃)₂CH CH₂ 4-Cl—Ph 2 3,9 412.1 148 F (CH₃)₂CH S3-Br-4-Cl—Ph 2 3 510 149 F (CH₃)(CH₂═)C C(O) 4-Cl—Ph 2 3,10 424.2 150 FCH₃S(O)₂ C(O) 6-Cl—Pyr 2 2 463.0 151 F CH₃S(O)₂ C(O) 3,4-diCl—Ph 2 2496.0 152 F CH₃S(O)₂ C(O) 4-nBu-Ph 2 2 500.2 153 F CH₃S(O)₂ C(O) 4-Ph-Ph2 2 504.3 154 PhCH₂O CH₃S(O)₂ S 4-Cl—Ph 2 6 554 155 PhCH₂S CH₃S(O)₂ S4-Cl—Ph 1 13  556 156 F CH₃S(O)₂ C(O) 4-Cl—Ph 2 2 462.1

What is claimed is:
 1. A compound having the formula I:

and pharmaceutically acceptable salts and hydrates thereof, wherein: R¹, R² and R³ are each independently selected from hydrogen and R^(g); R⁴ is selected from H, CN, C₁₋₆alkyl optionally substituted with one to six halogen, OR^(a) and S(O)_(n)C₁₋₆alkyl; R⁵ is selected from H and C₁₋₆alkyl optionally substituted with one to six halogen; R⁴ and R⁵ together represent an oxo; or R⁴ and R⁵ taken together form a 3- or 4-membered ring containing 0 or 1 heteroatom selected from NR^(f), S, and O optionally substituted with one or two groups selected from F, CF₃ and CH₃; R⁶ is selected from H and C₁₋₆alkyl optionally substituted with one to six groups independently selected from OR^(a) and halogen, Ar is aryl or heteroaryl each optionally substituted with one to four groups independently selected from R^(g); A is C₁₋₃alkyl optionally substituted with one to four halogen atoms, O(CH₂)12, S(CH₂)₁₋₂; Q is selected from: (1) COOH, (2) CONR^(a)R^(b), (3) C(O)NHSO₂R^(c), (4) SO₂NHR^(a), (5) SO₃H, (6) PO₃H₂, and (7) tetrazolyl, Y¹ is —(CR^(d)R^(e))_(a)—X—(CR^(d)R^(e))_(b)—, phenylene, C₃₋₆cycloalkylidene or C₃₋₆cycloalkylene, wherein a and b are integers 0-1 such that the sum of a and b equals 0, 1 or 2; X is a bond, O, S, NR^(a), C(O), OC(O), C(O)O, C(O)NR^(a), OC(O)NR^(a), NR^(a)C(O), CR^(d)═CR^(e) or C≡C; Y² is CR^(d)R^(e), CR^(d)R^(e)—CR^(d)R^(e), or CR^(d)═CR^(e), R^(a) and R^(b) are independently selected from H, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, Cy and Cy C₁₋₁₀alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to six substituents independently selected from halogen, amino, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, aryl, heteroaryl, aryl C₁₋₄alkyl, hydroxy, CF₃, OC(O)C₁₋₄alkyl, OC(O)NR^(i)R^(i), and aryloxy; or R^(a) and R^(b) together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N-R^(f); R^(c) is selected from C₁₋₆alkyl optionally substituted with one to six halogen, aryl and heteroaryl, wherein said aryl and heteroaryl are optionally substituted with halogen, OC₁₋₆alkyl, C₁₋₆alkyl and wherein said alkyl is optionally substituted with one to six halogen; R^(d) and R^(e) are independently H, halogen, aryl, heteroaryl, C₁₋₆alkyl or haloC₁₋₆alkyl, or R^(f) is selected from H, C₁₋₆alkyl, haloC₁₋₆alkyl, Cy, C(O)C₁₋₆alkyl, C(O)haloC₁₋₆ alkyl, and C(O)-Cy, R^(g) is selected from (1) halogen, (2) CN, (3) C₁₋₆alkyl optionally substituted with one to eight groups independently selected from aryl, heteroaryl, halogen, NR^(a)R^(b), C(O)R^(a), C(OR^(a))R^(a)R^(b), SR^(a) and OR^(a), wherein aryl, heteroaryl and alkyl are each optionally substituted with one to six groups independently selected from halogen, CF₃, and COOH, (4) C₂₋₆alkenyl optionally substituted with one to six groups independently selected from halogen and OR^(a), (5) Cy (6) C(O)R^(a), (7) C(O)OR^(a), (8) CONR^(a)R^(b), (9) OCONR^(a)R^(b), (10) OC₁₋₆alkyl, wherein alkyl is optionally substituted with one to six substituents selected from halogen, aryl, heteroaryl, OH and OC(O)R^(a), (11) O-aryl (12) O-heteroaryl (13) S(O)_(n)C₁₋₆alkyl, wherein alkyl is optionally substituted with one to six substituents selected from halogen, aryl, heteroaryl, OH, and OC(O)R^(a), (14) S(O)_(n)aryl, (15) S(O)nheteroaryl, (16) —NR^(a)S(O)_(n)R^(b), (17) —NR^(a)R^(b), (18) —NR^(a)C(O)R^(b), (19) —NR^(a)C(O)OR^(b), (20) —NR^(a)C(O)NR^(a)R^(b), (21) S(O)_(n)NR^(a)R^(b), (22) NO₂, (23) C₅₋₈cycloalkenyl, wherein Cy is optionally substituted with one to eight groups independently selected from halogen, C(O)R^(a), OR^(a), C₁₋₃alkyl, aryl, heteroaryl and CF₃; R^(i) and R^(j) are independently selected from hydrogen, C₁₋₁₀alkyl, Cy and Cy-C₁₋₁₀alkyl; or R^(i) and R^(j) together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; Cy is selected from heterocyclyl, aryl, and heteroaryl; n is 0, 1 or
 2. 2. A compound of claim 1 wherein Y¹ is selected from a bond, O, S, NR^(a), CHR^(d), CHR^(d)CHR^(d), C(O), C(O)CHR^(d), phenylene, and C₃₋₆cycloalkylidene.
 3. A compound of claim 1 wherein Y¹ is selected from S, CH₂, and C(O).
 4. A compound of claim 1 wherein A is C₁₋₃alkyl optionally substituted with one to four halogen atoms and Q is COOH.
 5. A compound of claim 1 wherein A-Q is CH₂COOH.
 6. A compound of claim 1 wherein Y² is selected from CH₂ and CH₂CH₂.
 7. A compound of claim 1 wherein Ar is phenyl or naphthyl optionally substituted with one to three groups independently selected from halogen, aryl, S(O)_(n)C₁₋₆alkyl optionally substituted with one to six halogen, C₁₋₆alkyl optionally substituted with one to five halogen atoms, CN, CONR^(a)R^(b), and C(O)R^(a), where R^(a) and R^(b) are as defined in claim
 1. 8. A compound of claim 1 wherein Ar is phenyl optionally substituted with one to three groups independently selected from halogen, aryl, S(O)_(n)C₁₋₆alkyl optionally substituted with one to six halogen, C₁₋₆alkyl optionally substituted with one to five halogen atoms, CN, CONR^(a)R^(b), and C(O)R^(a), where Ra and R^(b) are as defined in claim
 1. 9. A compound of claim 1 wherein Ar is 4-chlorophenyl optionally substituted with a second halogen atom.
 10. A compound of claim 1 wherein R⁴ and R⁵ are each hydrogen.
 11. A compound of claim 8 wherein Y¹ is selected from C(O), S and CH₂, Y² is CH₂ or CH₂CH₂, R⁴ and R⁵ are each hydrogen, and A-Q is CH₂COOH.
 12. A compound of claim 9 wherein Y¹ is selected from C(O), S and CH₂, Y² is CH₂ or CH₂CH₂, R⁴ and R⁵ are each hydrogen, and A-Q is CH₂COOH.
 13. A compound of claim 1 wherein R¹, R² and R³ are independently selected from hydrogen, CN, halogen, S(O)_(n)C₁₋₃alkyl, OC₁₋₆alkyl (optionally substituted with one to six substituents selected from halogen, aryl, heteroaryl, OH and OC(O)R^(a)), C₁₋₆alkyl (optionally substitued with one to eight groups selected from aryl, heteroaryl, halogen, NR^(a)R^(b), C(O)R^(a), C(OR^(a))R^(a)R^(b), SR^(a), and OR^(a), wherein aryl, heteroaryl and allyl are each optionally substituted with one to six groups independently selected from halogen, CF₃, and COOH), Cy, C₂₋₆alkenyl (optionally substituted with one to six groups independently selected from halogen and OR^(a)), C(O)OC₁₋₃alkyl, S(O)_(n)NR^(a)R^(b), C(O)R^(a), C(OH)R^(a)R^(b), C₅₋₈cycloalkenyl, and C(OC₁₋₃alkyl)R^(a)R^(b), wherein Cy is optionally substituted with one to eight groups independently selected from halogen, C(O)R^(a), OR^(a), C₁₋₃alkyl, aryl, heteroaryl and CF₃; n=0, 1 or 2; R^(a) and R^(b) are independently selected from hydrogen and C₁₋₆alkyl optionally substituted with halogen.
 14. A compound of claim 13 wherein one of R¹, R² and R³ is hydrogen.
 15. A compound of claim 1 having the formula Ia:


16. A compound of claim 15 wherein R¹, R² and R³ are independently selected from hydrogen, CN, halogen, S(O)_(n)C₁₋₃alkyl, OC₁₋₆alkyl (optionally substituted with one to six substituents selected from halogen, aryl, heteroaryl, OH and OC(O)R^(a)), C₁₋₆alkyl (optionally substitued with one to eight groups selected from aryl, heteroaryl, halogen, NR^(a)R^(b), C(O)R^(a), C(OR^(a))R^(a)R^(b), SR^(a), and OR^(a), wherein aryl, heteroaryl and alkyl are each optionally substituted with one to six groups independently selected from halogen, CF₃, and COOH), Cy, C₂₋₆alkenyl (optionally substituted with one to six groups independently selected from halogen and OR^(a)), C(O)OC₁₋₃alkyl, S(O)_(n)NR^(a)R^(b), C(O)R^(a), C(OH)R^(a)R^(b), C₅₋₈cycloalkenyl, and C(OC₁₋₃alkyl)R^(a)R^(b), wherein Cy is optionally substituted with one to eight groups independently selected from halogen, C(O)R^(a), OR^(a), C₁₋₃alkyl, aryl, heteroaryl and CF₃; n=0, 1 or 2; R^(a) and R^(b) are independently selected from hydrogen and C₁₋₆alkyl optionally substituted with halogen.
 17. A compound of claim 16 wherein R¹ is hydrogen and A-Q is CH₂COOH.
 18. A compound of claim 17 wherein R² is selected from halogen, S(O)_(n)C₁₋₃alkyl, OC₁₋₆alkyl (optionally substituted with aryl), CN, C₂₋₆alkenyl, 1- and 2-methyltetrazolyl, 1-methylpyrrolyl and C₁₋₆alkyl.
 19. A compound of claim 17 wherein R³ is selected from halogen, S(O)_(n)C₁₋₃alkyl, OC₁₋₆alkyl, C(O)R^(a), Cl₆alkyl (optionally substitued with 3 to 6 halogen atoms, and 0 or 1 group selected from OR^(a), SR^(a)), C₂₋₆alkenyl, C₅₋₈cycloalkenyl, phenyl (optionally substituted with a group selected from C₁₋₃alkyl, OR^(a) and pyrazolyl), naphthyl, and heteroaryl selected from pyrrolyl, thienyl, pyrazolyl, quinolinyl, benzothienyl, isoxalyl, pyridyl, each of which is optionally substituted with C₁₋₃alkyl.
 20. A compound of claim 1 having the formula Ib:

wherein Y¹ is O, S, C(O) or CH₂, R⁴ and R⁵ are each hydrogen or R⁴ and R⁵ together represent oxo, and R² and R³ represent one or two non-H substituent.
 21. A compound of claim 20, wherein R⁴ and R⁵ are each hydrogen, R² is selected from halogen, S(O)_(n)C₁₋₃alkyl, OC₁₋₆alkyl (optionally substituted with aryl), CN, C₂₋₆alkenyl, 1- and 2-methyltetrazolyl, 1-methylpyrrolyl and C₁₋₆alkyl, R³ is selected from halogen, S(O)_(n)C₁₋₃alkyl, OC₁₋₆alkyl, C(O)R^(a), C₁₋₆alkyl (optionally substitued with 3 to 6 halogen atoms, and 0 or 1 group selected from OR^(a), SR^(a),), C₂₋₆alkenyl, C₅₋₈cycloalkenyl, phenyl (optionally substituted with a group selected from C₁₋₃alkyl, OR^(a) and pyrazolyl), naphthyl, and heteroaryl selected from pyrrolyl, thienyl, pyrazolyl, quinolinyl, benzothienyl, isoxalyl, pyridyl, each of which is optionally substituted with C₁₋₃alkyl, and Ar is selected from 1- and 2-napthyl, phenyl (optionally substituted with one to three groups independently selected from halogen, aryl, S(O)_(n)C₁₋₆alkyl optionally substituted with one to six halogen, C₁₋₆alkyl optionally substituted with one to five halogen atoms, CN, CONR^(a)R^(b), and C(O)R^(a), where R^(a) and R^(b) are as defined in claim 1), and heteroaryl selected from furyl, pyridyl, benzothiazolyl, quinolinyl and pyrimidinyl, each optionally substituted with one or two halogen atoms.
 22. A compound of claim 1 having the formula Ic:

wherein Y¹ is C(O), CH₂ or S, R and R′ are independently hydrogen, halogen, cyano, C₁₋₃alkanoyl or CF₃, R² is selected from halogen, S(O)_(n)C₁₋₃alkyl, OC₁₋₆alkyl (optionally substituted with aryl), CN, C₂₋₆alkenyl, 1- or 2-methyltetrazolyl, 1-methylpyroolyl and C₁₋₆alkyl, and R³ is selected from halogen, S(O)_(n)C₁₋₃alkyl, OC₁₋₆alkyl, C(O)R^(a), C₁₋₆alkyl (optionally substitued with 3 to 6 halogen atoms, and 0 or 1 group selected from OR^(a), SR^(a),), C₂₋₆alkenyl, C₅₋₈cycloalkenyl, phenyl (optionally substituted with a group selected from C₁₋₃alkyl, OR^(a) and pyrazolyl), naphthyl, and heteroaryl selected from pyrrolyl, thienyl, pyrazolyl, quinolinyl, benzothienyl, isoxalyl, pyridyl, each of which is optionally substituted with C₁₋₃alkyl.
 23. A compound of claim 22 wherein R² is F, R is Cl, R′ is hydrogen, and R³ is selected from halogen, S(O)_(n)C₁₋₃alkyl, OC₁₋₆alkyl, C(O)R^(a), C₁₋₆alkyl (optionally substitued with 3 to 6 halogen atoms, and 0 or 1 group selected from OR^(a), SR^(a),), C₂₋₆alkenyl, C₅₋₈cycloalkenyl, phenyl (optionally substituted with a group selected from C₁₋₃alkyl, OR^(a) and pyrazolyl), naphthyl, and heteroaryl selected from pyrrolyl, thienyl, pyrazolyl, quinolinyl, benzothienyl, isoxalyl, pyridyl, each of which is optionally substituted with C₁₋₃alkyl.
 24. A compound selected from

R² R³ Y¹ Ar p H H CH₂ 4-Cl—Ph 2 H H CH₂ 4-Cl—Ph 1 H H S 4-Cl—Ph 2 CH₃S(O)₂ H S 4-Cl—Ph 2 H CH₃S(O) — 4-Cl—Ph 2 H CH₃S(O) CH₂ 4-Cl—Ph 2 F Br S 4-Cl—Ph 1 F Br S 4-Cl—Ph 2 CH₃S(O)₂ CH₃O S 4-Cl—Ph 2 F CH₃C(O) S 4-Cl—Ph 1 F CF₃C(O) S 4-Cl—Ph 1 F CF₃CH(OH) S 4-Cl—Ph 1 F (CH₃)₂CHCH(OH) S 4-Cl—Ph 1 F CH₃CH(OH) S 4-Cl—Ph 1 F CH₃CH(OCH₃) S 4-Cl—Ph 1 F CH₃C(O) S Ph 1 F CH₃C(O) S 3,4-diCl—Ph 1 F CF₃CH(OCH₃) S 4-Cl—Ph 1 F CH₃CH₂CH(OH) S 4-Cl—Ph 1 F CH₃CH₂CH(OCH₃) S 4-Cl—Ph 1 F CH₃CH(SCH₃) S 4-Cl—Ph 1 CH₃O CH₃S(O)₂ S 4-Cl—Ph 1 PhCH₂O CH₃S(O)₂ S 4-Cl—Ph 1 CH₃S CH₃(O)₂ S 4-Cl—Ph 1 CH₃S(O)₂ (CH₃)₂CH S 4-Cl—Ph 1 (CH₃)₂CHO CH₃S(O)₂ S 4-Cl—Ph 1 PhCH₂O (CH₃)₂CH S 4-Cl—Ph 1 CH₃O (CH₃)₂CH S 4-Cl—Ph 1 4-Cl—Ph CH₃S(O)₂ S 4-Cl—Ph 1 I Br S 4-Cl—Ph 1 CN Br S 4-Cl—Ph 1 2-CH₃-5-Tz# Br S 4-Cl—Ph 1 1-CH₃-5-Tz Br S 4-Cl—Ph 1 1-CH₃-2-pyrrolyl Br S 4-Cl—Ph 1 CN CH₃C(O) S 4-Cl—Ph 1 2-CH₃-5-Tz CH₃C(O) S 4-Cl—Ph 1 F CH₃S(O)₂ S 4-Cl—Ph 1 F CH₃CH₂S(O)₂ S 4-Cl—Ph 1 p 1-CH₃-2-pyrrolyl S 4-Cl—Ph 1 F CH₃CH₂CH₂ S 4-Cl—Ph 1 F CH₃CH₂ S 4-Cl—Ph 1 F CH₃C(═CH₂) S 4-Cl—Ph 1 F 1-CH₃-5-pyrazolyl S 4-Cl—Ph 1 F (CH₃)₂CH S 4-Cl—Ph 1 F 1-cyclopentenyl S 4-Cl—Ph 1 F (CH₃CH═)(CH₃CH₂)C S 4-Cl—Ph 1 F (CH₃CH₂)₂CH S 4-Cl—Ph 1 F cyclopentyl S 4-Cl—Ph 1 F Ph S 4-Cl—Ph 1 F 2-thienyl S 4-Cl—Ph 1 F 3-CH₃-2-thienyl S 4-Cl—Ph 1 F CH₂═CH S 4-Cl—Ph 1 CH₂═CH Br S 4-Cl—Ph 1 F (CF₃)₂C(OH) S 4-Cl—Ph 1 F 3-thienyl S 4-Cl—Ph 1 cyclopropyl 1-CH₃-2-pyrrolyl S 4-Cl—Ph 1 2-CH₃-5-Tz 1-CH₃-2-pyrrolyl S 4-Cl—Ph 1 2-CH₃-5-Tz Ph S 4-Cl—Ph 1 F cyclopropyl S 4-Cl—Ph 1 F Br CH₂ 4-Cl—Ph 1 F CH₃S(O)₂ CO 4-Cl—Ph 1 F CH₃S(O)₂ CH₂ 4-Cl—Ph 1 F (CF₃)₂C(OCH₃) S 4-Cl—Ph 1 F (CH₃)₂CH C(O) 4-Cl—Ph 1 F 1-CH₃-2-pyrrolyl 4-Cl—Ph 1 F (CH₃)₂CH CH₂ 4-Cl—Ph 1 F CH₃S(O)₂ CH₂ 2,4-diCl—Ph 1 F CH₃S(O)₂ CH₂ 2,6-diCl—Ph 1 F Br 4-Cl—Ph 1 F cyclopropyl 4-Cl—Ph 1 F (CH₃O)(CH₃CH₂)CH C(O) 4-Cl—Ph 1 F Ph 4-Cl—Ph 1 F 2-thienyl 4-Cl—Ph 1 F CH₃S(O)₂ CH₂ 2,4,6-triCl—Ph 1 F CH₃S(O)₂ S 2,4,5-triCl—Ph 1 F CH₃S(O)₂ C(O) 4-biphenyl 1 F CH₃S(O)₂ C(O) 2-naphthyl 1 F Br C(O) 2-naphthyl 1 *F CH₃S(O)₂ S 4-Cl—Ph 1 F CH₃S(O)₂ C(O) 2-furyl 1 F CH₃S(O)₂ C(O) 2,4-diCl—Ph 1 F CH₃S(O)₂ C(O) 4-Cl-2-CH₃S(O)₂-Ph 1 F Br C(O) 4-Cl-2-I—Ph 1 F Br C(O) 4-Cl-2-CONH₂-Ph 1 F CH₃S(O)₂ C(O) 4-Cl-2-CN—Ph 1 F (CH₃)₂CH C(O) 4-Cl-2-I—Ph 1 F Br C(O) 2-benzothiazolyl 1 F (CH₃)₂CH C(O) 4-Cl-2-CH₃S(O)₂-Ph F CH₃S(O)₂ S 4-CF₃-Ph 1 F CH₃S(O)₂ S 4-CH₃S(O)₂-Ph 1 F Br C(O) 2-quinolinyl 1 F CH₃S(O)₂ C(O) 2-quinolinyl 1 F Br S 2-benzothiazolyl 1 F CH₃S(O)₂ S 2-benzothiazolyl 1 2-CH₃-5-Tz CH₃S(O)₂ S 4-Cl—Ph 1 F CH₃S(O)₂ CH(CH₃) 4-Cl—Ph 1 F CH₃S(O)₂ C(O)CH₂** 4-Cl—Ph 1 F (CH₃)₂CH S 1-naphthyl 1 F (CH₃)₂CH S 2-naphthyl 1 F Br S 2-pyrimidinyl 1 F CH₃S(O)₂ S 2-pyrimidinyl 1 F CH₃S(O)₂ CH₂CH₂ 4-Cl—Ph 1 2-CH₃-5-Tz (CH₃O)(CH₃CH₂)CH S 4-Cl—Ph 1 F (CH₃)₂CH C(O) 2-naphthyl 1 F CH₃S(O)₂ S 2-naphthyl 1 F (CH₃)₂CH S 4-Cl-2-F—Ph 1 F CH₃S(O)₂ S 4-Cl-2-F—Ph 1 F 2-CH₃-Ph S 4-Cl—Ph 1 F 8-quinolinyl S 4-Cl—Ph 1 F 3-benzothienyl S 4-Cl—Ph 1 F 3,5-diCH₃-4-isoxalyl S 4-Cl—Ph 1 F 4-CH₃-3-thienyl S 4-Cl—Ph 1 F 3-(1-pyrazolyl)-Ph S 4-Cl—Ph 1 F 2-(HC(O))-3-thienyl S 4-Cl—Ph 1 F 2-OCH₃-Ph S 4-Cl—Ph 1 F 3,4-diCl—Ph S 4-Cl—Ph 1 F 6-quinolinyl S 4-Cl—Ph 1 F 2-naphthyl S 4-Cl—Ph 1 F CN S 4-Cl—Ph 1 F (CH₃)₂CH C(O) 1-naphthyl 1 F (CH₃)₂CH C(O) 3,4-diCl—Ph 1 F (CH₃)₂CH S 4-Cl—Ph 2 F (CH₃)₂CH C(O) 2-nahthyl 2 F (CH₃)₂CH C(O) 4-Cl—Ph 2 F CH₃S(O)₂ S 4-Cl—Ph 2 F CH₃S(O)₂ 1,4-phenylene Ph 1 F CH₃S(O)₂ — 2-naphthyl 1 F CH₃S(O)₂ 1,3-phenylene Ph 1 CN (CH₃)₂CH S 4-Cl—Ph 1 2-CH₃-5-Tz (CH₃)₂CH S 4-Cl—Ph 1 1-CH₃-5-Tz (CH₃)₂CH S 4-Cl—Ph 1 CH₃S(O)₂ CH₃S(O)₂ S 4-Cl—Ph 1 H 1-CH₃-2-pyrrolyl S 4-Cl—Ph 1 F 3-pyridyl S 4-Cl—Ph 1 F CH₃S(O)₂ S 4-Cl—Ph 2 F CH₃S(O)₂ S 2-naphthyl 2 F (CH₃)₂CH C(O) 3-Br-4-Cl—Ph 2 F (CH₃)₂CH CH₂ 4-Cl—Ph 2 F (CH₃)₂CH S 3-Br-4-Cl—Ph 2 F (CH₃)(CH₂═)C C(O) 4-Cl—Ph 2 F CH₃S(O)₂ C(O) 6-Cl-Pyr## 2 F CH₃S(O)₂ C(O) 3,4-diCl—Ph 2 F CH₃S(O)₂ C(O) 4-nBu—Ph 2 F CH₃S(O)₂ C(O) 4-Ph—Ph 2 PhCH₂O CH₃S(O)₂ S 4-Cl—Ph. 2 PhCH₂S CH₃S(O)₂ S 4-Cl—Ph 1 F CH₃S(O)₂ C(O) 4-Cl—Ph 2

and R¹ R² R³ A—Q F F 1-CH₃-2-pyrrolyl CH₂CO₂H F F CH₃S(O)₂ CH₂CO₂H F F S-(4-Cl-Ph) CH₂CO₂H CH₃S(O)₂ F CH₃S(O)₂ CH₂CO₂H CH₃S(O)₂ CH₃O CH₃S(O)₂ CH₂CO₂H F H CH₃S(O)₂ CH₂CO₂H H F Br CF₂CO₂H *H F Br CF₂CO₂H H F CH₃S(O)₂ CF₂CO₂H


25. A pharmaceutical composition comprising a compound salt or hydrate of any one of claims 1 to 24, and a pharmaceutically acceptable carrier.
 26. The composition of claim 25 further comprising a second active ingredient selected from an antihistamine, a leukotriene antagonist and a leukotriene biosynthesis inhibitor.
 27. A method for the treatment of prostaglandin D2 mediated diseases which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim
 1. 28. A method for the treatment of nasal congestion which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim
 1. 29. A method for the treatment of allergic asthma which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim
 1. 30. A method for the treatment of allergic rhinitis which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim
 1. 31. A pharmaceutically acceptable salt or hydrate of a compound of formula I, as defined in any one of claims 1 to
 23. 32. Use of a compound of formula I, as defined in any one of claims 1 to 23, or a pharmaceutically acceptable salt or hydrate thereof in the manufacture of a medicament for the treatment of prostaglandin D2 mediated diseases.
 33. Use of a compound of formula I, as defined in any one of claims 1 to 23, or a pharmaceutically acceptable salt or hydrate thereof, in the manufacture of a medicament for the treatment of nasal congestion, allergic asthma or allergic rhinitis.
 34. A compound of formula I, as defined in any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof for use in the treatment of prostaglandin D2 mediated diseases.
 35. A compound of claim 24, or a pharmaceutically acceptable salt or hydrate thereof, for use in the treatment of nasal congestion, allergic asthma or allergic rhinitis.
 36. A prostaglandin D2 receptor antagonist pharmaceutical composition comprising an acceptable prostaglandin D2 receptor antagonistic amount of a compound of formula L as defined in any one of claims 1 to 23, or a pharmaceutically acceptable salt or hydrate thereof, in association with a pharmaceutically acceptable carrier. 